HUP0200055A2 - 16-hydroxyestrienes and pharmaceutical compositions containing the same - Google Patents

Abstract

The subject of the invention are: (I) compounds of the general formula as medicinal active substances, which exert an effect on bones and/or show an effect on stimulating the expression of the 5HT2a receptor and transporter, and medicinal preparations of various preparations containing the new compounds. The compounds of general formula (I) are new types of 16a- and 16b-hydroxyestra-1,3,5/10/-estratrienes, which carry additional substituents on the steroid skeleton and may contain one or more additional double bonds in the B, C and/or D ring . HE

Description

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The invention relates to compounds as pharmaceutical active ingredients which, in vitro, show higher activity against estrogen receptor preparations derived from rat prostate than against estrogen receptor preparations derived from rat uterus and in vivo exert a preferentially pronounced effect on bones compared to the uterus and/or show a pronounced effect on stimulating the expression of the 5HT2a receptor and transporter; their preparation, therapeutic use and pharmaceutical preparations of various formulations containing the novel compounds.

The compounds are a new type of tissue-selective steroidal estrogens.

Estrogen therapy has previously been developed to treat hormone deficiency complaints, and it is known that estrogens have a protective effect on bones, brain, blood vessels, and other organ systems.

The efficacy of estrogens in the treatment of hormone deficiency symptoms (e.g. hot flashes, atrophy of estrogen target organs, and incontinence) is well known, as is the successful use of estrogen therapy to inhibit bone loss in peri- and menopausal women, and these effects are generally expected (Grady et al.: Ann.Intern.Med. 117, 1016-1037, 1992).

There is also a large body of literature (1. the previous reference) that estrogen replacement therapy in women after menopause or with ovarian failure due to other causes reduces the risk of circulatory diseases compared to women not treated with estrogens (1. the previous reference).

Based on recent studies, it can also be assumed that estrogens have a protective effect against neurodegenerative diseases, such as Alzheimer's disease /Henderson: Neurology 48, Suppl. 7, 527-535, 1997; Birge, ibid., 36-41/; on brain functions, such as memory impairment and learning ability /MCewan et al., ibid., 8-15; Sherwin, ibid., 21-26/, and against mood swings caused by hormone deficiency /Halbreich, ibid., 16-29/.

It can also be mentioned that estrogen replacement therapy has been shown to be effective in reducing the incidence of colon carcinoma /Calle et al., J. Nai. Cancer Inst. 87, 17-23, 1995/.

In the case of traditional estrogen and hormone replacement therapy (HRT), natural estrogens are used, such as estradiol and conjugated estrogens isolated from horse urine, alone or in combination with a progestogen. Derivatives formed by esterification, such as 17β-estradiol valerate, can also be used instead of natural estrogens.

The estrogens used have a stimulating effect on the endometrium, which leads to an increased risk of endometrial carcinoma /Harlap: Am.J.Obstet. Gynecol. 166, 1986-1992, 1992/. Therefore, estrogen/gestagen combination preparations are preferably used in hormone replacement therapy. The gestagen

...· ·..· .:. —· .component in the estrogen/gestagen combination results in the avoidance of endometrial hypertrophy; otherwise, the use of a preparation containing a gestagen is accompanied by the occurrence of unwanted temporary bleeding.

Selective estrogens represent a new alternative to estrogen/gestagen combination preparations. Selective estrogens were previously understood as compounds that act similarly to estrogens on the brain, bones, and vascular system, but due to their antiuterotrophic (i.e. antiestrogenic) partial effect, do not promote endometrial proliferation.

A class of substances that partially exhibit the desired effect of a selective estrogen are the "selective estrogen receptor modulators (SERMs)" /Kauffman et al., DNAP 8(9), 531-539, 1995/. They are partial antagonists of the estrogen receptor subtype "ERa". This type of substance is otherwise ineffective in the treatment of acute postmenopausal symptoms - such as hot flashes. An example of a SERM is raloxifene, which was temporarily introduced in the field of osteoporosis.

Recently, the β-estrogen receptor /ΕΚβ/ has been recognized as the second subtype of the estrogen receptor /Kuiper et al.: Proc. Natl.Acad.Sci. 93, 5925-5930, 1996; Mosselman et al.: FEBS Letters 392, 49-53, 1996; Tremblay et al.: Molecular Endocrinology 11, 353-365, 1997/. The expression pattern of ΕΡβ differs from that of ERα /Kuiper et al., Endocrinology 138, 863-870, 1996/. Thus, in the rat prostate, ΕΚβ is predominant over ERα, while in the rat uterus the situation is reversed. Isolated in the brain ··· · · · · · · · · · · ...· *..· .:. —· .areas in which only one ER subtype is always expressed /Shugrue et al.: Steroids 61, 678-681, 1996; Li et al.: Neuroendocrinology 66, 63-67, 1997/. ΕΗβ is expressed, among others, in areas that are considered important for cognitive processes and “mood” /Shugrue et al.: Comparative Neurology 388, 507-525, 1997/.

The molecular target for ΕΗβ in these brain areas could be the 5HT2a receptor and the serotonin transporter /Fink et al.: Nature 383, 306, 1996; Sumner et al.: Molecular Brain

Research, in press. The neurotransmitter serotonin (5-hydroxytryptamine) plays a role in the regulation of many processes that may arise in connection with menopause. The serotonin system is particularly associated with the effects of menopause on mood and learning processes. Estrogen replacement therapy has been shown to be effective in treating these estrogen-deficient conditions, possibly by modulating serotonin receptor and transporter expression.

Other organ systems with relatively high EHβ expression include:

bones /Onoe et al.: Endocrinology 138, 4509-4512, 1997/ the circulatory system /Register et al: J.Steroids Mol.Biology 64, 187191, 1998/ the urogenital tract /Kuiper et al.: Endocrinology 138, 863870, 1996/ the gastrointestinal tract /Campbell-Thopson: BBRC 240, 478-483, 1997/ and the testis /Mosseelmann et al.: FEBS Letters 392, 49-53, 1996/ including spermatids /Shugrue et al.: Steroids 63, 498-504, 1998/.

Based on the tissue distribution, it is clear that estrogens regulate ΕΚβ organ functions. That ΕΚβ plays a functional role in this regard is also evident from studies conducted with ERα-/ERK0/ or ΕΚβ-/ΒΕΚΚΟ/-knockout mice. Ovariectomy causes bone loss in ERKO mice, which can be reversed by estrogen replacement /Kimbro et al.: Endocrine Society Meeting, Abstract 0R7-4, New Orleans, 1998/. Estradiol also inhibits cell proliferation in the vascular and smooth muscle cells in the circulation of female ERKO mice /lafrati et al. : Nature Medicine 3, 545-548, 1997/. These protective effects of estradiol in ERKO mice are presumably mediated by ΕΚβ.

Observations in ERKO mice point to a function of ΕΚβ in the prostate and bladder: symptoms suggestive of prostate and bladder hypertrophy occur in older male mice /Krege et al.: Proc.Natl.Acad.Sci. 95, 15677-15682, 1998/. In addition, reproductive disorders occur in female /Lubahn et al.: Proc.Natl.Acad.Sci. 90, 11162-11166, 1993/ and male /Hess et al.: Nature 390, 509-512, 1997/ ERKO mice, as well as in female BERKO mice /Krege, loc.cit./. All of this suggests that estrogens play an important role in maintaining testicular and ovarian function, as well as fertility.

It is described (Westerlind et al.: J. Bone and Mineral Res. 13, 1023-1031, 1998) that 16α-hydroxyestrone exerts differential effects on bones and reproductive organs in female rats.

Our own studies indicate that 16a-hydroxyestrone binds three times more strongly to the human β estrogen receptor /ERp/ than to the human α estrogen receptor /ERa/. The RBA value of the substance for the rat prostate estrogen receptor is five times greater than the BA value for the rat uterine estrogen receptor. The distribution of action /dissociation/ of the substance described by Westerlind can be traced, based on our own knowledge, to a preference for ERp over ERa.

Selective estrogenic effects on specific target organs would be achieved by the differential distribution of specific ligands for the two ER subtypes in tissues and organs. Substances that prefer ERβ over ERα in in vitro receptor binding assays have been described (Kuiper, loc. cit.). So far, selective effects of estrogen receptor subtype-specific ligands on estrogen-specific parameters have not been demonstrated in vivo.

The object of the invention is therefore to find compounds which show a difference in activity (dissociation) in vitro with respect to binding to estrogen receptor preparations prepared from rat prostate and rat uterus and which show a preferential dissociation in vivo with respect to the effect on bone compared to the effect on the uterus. The compounds should have a higher affinity in vitro for estrogen receptor preparations prepared from rat prostate than for estrogen receptor preparations prepared from rat uterus and preferably show a higher potency in vivo against bone loss caused by hormone deficiency than for the uterine stimulating effect and/or a pronounced effect in stimulating the expression of the 5HT2a receptor and transporter.

In the following, we point out that according to the invention, in a broader sense, we have found a structure/effect relationship, through which we can obtain compounds that have the pharmacological profile stated above /better effect on bones than on the uterus/.

According to the invention, the aforementioned object is achieved by using 16α- and 16β-hydroxy-estra1,3,5/10/-trienes of general formula (I) for the preparation of pharmaceutical compositions for the treatment of diseases and conditions caused by estrogen deficiency. In this formula, the meanings of the substituents independently of each other are as follows:

R is a halogen atom, a hydroxy, methyl, trifluoromethyl, methoxy, ethoxy group or a hydrogen atom,

R is a halogen atom, a hydroxy group, a straight or branched chain, saturated or unsaturated alkoxy group with up to 6 carbon atoms, or a hydrogen atom,

R ⁴ is a halogen atom, a straight or branched chain, saturated or unsaturated alkyl group with up to 10 carbon atoms, a trifluoromethyl or pentafluoroethyl group, a straight or branched chain, up to 6 carbon atoms

^R8

R ⁹

R ¹¹ is a branched, saturated or unsaturated alkoxy group or _hydrogen atom, a halogen atom in the α- or β-position, a straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl group in the α- or β-position, having up to 10 carbon atoms, an unsaturated straight or branched, saturated or branched, optionally partially or fully fluorinated alkyl group in the α- or β-position, an unsaturated straight or branched, saturated or branched, optionally substituted aryl or heteroaryl group or hydrogen atom, or a hydrogen atom in the β-position, an alkyl group in the α- or β-position, having up to 6 carbon atoms, an alkyl group in the α- or β-position, having up to 10 carbon atoms, an alkyl group in the α- or β-position, having up to 6 A straight or branched chain alkyl group with up to 10 carbon atoms, optionally partially or saturated or saturated fluorinated, or a chloro group in the α- or β-position, or a hydrogen atom in the β-position, a methyl, ethyl, trifluoromethyl or pentafluoroethyl group in the α- or β-position, a nitroxy, hydroxy or mercapto group in the α- or β-position, a halogen atom in the α- or β-position, a chloromethyl group in the α- or β-position, or a branched « or β-position alkyl group with up to 10 carbon atoms, saturated or unsaturated, optionally partially or fully fluorinated.

max.

carbon-containing straight or branched, saturated or unsaturated alkoxyR ¹³ or alkylthio group, optionally substituted aryl or heteroaryl group or hydrogen atom, α- or β-position _methyl , _{trifluoromethyl} .

fluoroethyl group, and

R ¹⁴ is a straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkyl group with up to 10 carbon atoms in the α- or β-position or a hydrogen atom in the α- or β-position,

R ¹⁵ is a halogen atom in the α- or β-position, a straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkyl group of up to 10 carbon atoms in the α- or β-position, which may be interrupted by one or more oxygen, sulfur, sulfoxide or sulfone groups or an imino group of the formula =NR ¹⁵ ', or a hydrogen atom,

R ¹⁵ ' represents a hydrogen atom, a methyl, ethyl, propyl or i-propyl group, or

R ¹⁴ and R ¹⁵ together represent a 14α,15α-methylene or 14β-15β-methylene group optionally substituted with 1 or 2 halogen atoms,

R ¹⁶ is a hydrogen atom in the α- or β-position, a straight-chain or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl group with up to 10 carbon atoms in the α- or β-position, a trifluoromethyl or pentafluoroethyl group, a cyanomethyl group,

R ¹⁷ is a halogen atom in the α- or β-position, a straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkyl group with up to 10 carbon atoms, a hydrogen atom or a hydroxyl group, in which formula the dotted line in the B, C and D rings optionally represents one or more double bonds, while the wavy line indicates that the given substituent is in the α- or β-position.

According to one embodiment of the invention, compounds of general formula (I) are preferably used in which R 1 -R 17 independently have the following meanings:

R ¹ is a fluorine atom, a hydroxy, methyl, trifluoromethyl, methoxy, ethoxy group or a hydrogen atom,

R is a fluorine atom, a hydroxy, methoxy, ethoxy group or a hydrogen atom, R ⁴ is a fluorine atom, a methyl, ethyl, trifluoromethyl, methoxy, ethoxy group or a hydrogen atom,

R ⁷ is a fluorine atom in the α- or β-position, a methyl, ethyl, propyl or i-propyl group in the α- or β-position, an optionally substituted aryl group, a trifluoromethyl group in the α- or β-position or a hydrogen atom,

R ⁸ is a hydrogen atom in the α- or β-position, a methyl or ethyl group in the α- or β-position,

R ⁹ is a hydrogen atom in the α- or β-position, a methyl, ethyl, trifluoromethyl or pentafluoromethyl group in the α- or β-position,

R ¹¹ is a nitroxy, hydroxy group or fluorine atom in the α- or β-position, a chloromethyl group in the α- or β-position, a methyl—, — methoxy—, phenyl— or 3—methyl—thien-2—yl group in the α- or β-position or a hydrogen atom, ^{r13 is a methyl or ethyl group in the} “ or β-position, and 14 _Λ

R is a hydrogen atom in the α- or β-position or a methyl group in the α- or β-position and

R ¹⁵ is a fluorine atom in the α- or β-position, a methyl group in the α- or β-position or a hydrogen atom, or

R ¹⁴ and R ¹⁵ together are a 14α, 15α— methylene— or 14β,15β inethylene group,

R ¹⁶ is methyl, ethyl, ethynyl, propynyl or trifluoromethyl,

R ¹⁷ is a fluorine atom in the α- or β-position, a methyl group, a hydroxy group or a hydrogen atom, and the dashed lines in rings B, C and D optionally represent an additional double bond between carbon atoms 9 and 11.

In addition to the use of the compounds of general formula (I) discussed above, the invention also relates to the compounds of general formula (I'). The latter are identical to the compounds of general formula (I) with the exception of the following: oestra-1,3,5/10/-triene-3,16a-diol, oestra-1,3,5/10/-triene-3,Ιδβ-diol, oestra-1,3,5/10/,7-tetraene-3,16α-diol, oestra-1,3,5/10/,7-tetraene-3,16β-diol, 16α-ethynyl-oestra-1,3,5/10/-triene-3,Ιδβ-diol and Ιδβ-ethynyl-oestra-1,3,5/10/-triene-3,16a-diol.

These latter compounds are already known, but their selective estrogenic effect and their use according to the invention have not yet been described.

16α-Hydroxy-17-methylene estrogen is described in WO 97/08188 as a compound with anti-inflammatory activity and suitable for the treatment of immunological diseases, especially autoimmune diseases.

The differential effect of 16a-hydroxyestrone has already been described by Westerling et al. /loc.cit./, on brain functions and the circulatory system.

...· ·..· .:. ...· ...· agent or the differentiated effect on the uterus is not mentioned.

3,16a-dihydroxyestradione has also been described as a "short-acting estrogen" (Stack et al., loc.cit.). However, its use as a selective estrogen is not yet known.

3,16-dihydroxyestradione substituted at the 16th position with an ethynyl group is described in FR 5099. The 16β-ethynyl derivative can be used as an agent against high cholesterol.

In the compounds of general formulae (I) and (I') and in the sub-structures (II) and (II') to be described below, a "halogen atom" always means a fluorine, chlorine, bromine or iodine atom; in each case, the fluorine atom is preferred.

In the compounds of general formulae (I) and (I'), as well as in the sub-structures (II) and (II') to be described below, the alkoxy groups may have 1-6 carbon atoms, such as the methoxy, ethoxy, propoxy, isopropoxy and tert-butoxy groups.

The alkylthio group may be, for example, methylthio, ethylthio and trifluoromethylthio.

The aryl group according to the invention means phenyl, 1- or 2-naphthyl, and phenyl is preferred.

Unless otherwise indicated, an aryl group can always represent a heteroaryl group. Examples of heteroaryl groups include one of the following: 2-, 3- or 4-pyridinyl, 2- or 3-furyl, 2- or 3-thienyl, 2- or 3-pyrrolyl, 2-, 4- or 5-imidazolyl, pyrazinyl, 2-, 4- or 5-pyrimidinyl or 3- or 4-pyridazinyl.

...· ./. ...· ...·

As substituents of the aryl or heteroaryl group, the following may be mentioned, for example: methyl, ethyl, trifluoromethyl, pentafluoroethyl, trifluoromethylthio, methoxy, ethoxy, nitro, cyano, a halogen atom (fluorine, chlorine, bromine or iodine atom), hydroxy, amino, mono- (C1-C8)-alkyl or di- (C1-C8)-alkylamino group (where the two alkyl groups are the same or different); di- (aralkyl)amino group, where the two aralkyl groups are the same or different.

As representatives of the straight or branched chain groups having 1 to 10 carbon atoms, the following may be mentioned: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl; methyl, ethyl, propyl and isopropyl are preferred.

The alkyl groups may be partially or fully fluorinated or substituted with 1 to 5 halogen atoms, hydroxy or (C1-C4)-alkoxy groups.

Perfluorinated alkyl groups include trifluoromethyl, pentafluoroethyl, and nonafluorobutyl. Examples of partially fluorinated alkyl groups include 2,2,2-trifluoroethyl, 5,5,5,4,4-pentafluoropentyl, 9,9,9,8,8,7,7,6,6-nonafluorohexyl, etc.

The halogen-substituted 14,15-methylene group may be a monochloromethylene, monofluoromethylene or difluoromethylene group. Further variations are possible in embodiments of the invention by introducing one or more conjugated double bonds in rings B, C and D of the estratriene skeleton, as shown below:

double bond between carbon atoms 6 and 7 or 7 and 8 or 8 and 9 or 9 and 11 or 8 and 14 or 14 and 15, or between carbon atoms 6 and 7 and 8 and 9, or between carbon atoms 8 and 9 and

between carbon atoms 14 and 15, or between carbon atoms 6 and 7, 8 and 9, and

between carbon atoms 11 and 12, or between carbon atoms 6 and 7, 8 and 9, and

between carbon atoms 14 and 15, or between carbon atoms 6 and 7, 8 and 9, 11 and 12, and 14 and 15.

One or both of the hydroxy groups on carbon atoms 3 and 16 may be esterified with an aliphatic, straight or branched chain, saturated or unsaturated mono- or polycarboxylic acid having 1 to 14 carbon atoms or with an aromatic carboxylic acid or with an α- or β-amino acid.

Such carboxylic acids suitable for esterification include, for example, the following: monocarboxylic acids: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovalerian acid, pivalic acid, lauric acid, myristic acid, acrylic acid, propioic acid, methacrylic acid, crotonic acid, isocrotonic acid, oleic acid, elaidic acid, dicarboxylic acids: oxalic acid, malonic acid, tartaric acid, glutaric acid, adipic acid, pimelic acid, parafic acid, azelaidic acid, sebacic acid, maleic acid, fumaric acid, muconic acid, citraconic acid, mesaconic acid, aromatic carboxylic acids: benzoic acid, phthalic acid, isophthalic acid, terephthalic acid, naphthoic acid, ο-, m- and p-toluic acid, hydratropic acid, atropactic acid, cinnamic acid, nicotinic acid, isonicotinic acid.

Suitable amino acids include representatives of this class of compounds known to the skilled person, e.g. the following: alanine, β

...............

...· .1.__’ .~· alanine, arginine, cysteine, cystine, glycine, histidine, leucine, isoleucine, phenylalanine, proline, etc.

In the compounds of the invention and in the sub-structures to be described below, the 16-oxy group may be in both the α- and β-positions.

According to one embodiment of the invention, in general formula (I), (I') and partial formulae (II')

R ⁷ is a halogen atom in the α- or β-position, an α- or β-position straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkyl group having up to 10 carbon atoms, a straight or branched chain, saturated or unsaturated alkoxy group having up to 6 carbon atoms or an optionally substituted aryl or heteroaryl group and all other substituents are hydrogen atoms.

According to another embodiment of the invention, in general formula (I), (I') and partial formulae (II')

R ¹¹ represents a nitroxy, hydroxy or mercapto group in the α- or β-position, a halogen atom in the α- or β-position, a chloromethyl group in the α- or β-position, a straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkyl group in the α- or β-position, a straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkoxy or alkylthio group in the α- or β-position, a straight or branched chain, saturated or unsaturated, having up to 6 carbon atoms, or an optionally substituted aryl or heteroaryl group and all other substituents represent a hydrogen atom.

According to a further embodiment of the invention, in the general formula (I), (I' ) and in the partial formulae (II') ··· · · · ··· ··· .·.· ·..· J· —- · . ' r ¹⁵ represents a halogen atom in the α- or β-position, a straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkyl group with up to 10 carbon atoms, which may be interrupted by one or more oxygen, sulfur atoms, sulfoxide or sulfone groups or a group of the formula =NR ¹⁵ , where

R ¹⁵ 'is hydrogen, methyl, ethyl, propyl or i-propyl, and all other substituents are hydrogen.

According to another embodiment of the invention, in general formula (I), (I') and partial formulae (II')

R ⁷ represents a halogen atom in the α- or β-position, a linear or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl group in the α- or β-position, a linear or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl group in the α- or β-position, a linear or branched, saturated or unsaturated, optionally partially or fully fluorinated alkoxy group in the α- or β-position, or an optionally substituted aryl or heteroaryl group, rü represents a nitroxr—, hydroxy or mercapto group in the α- or β-position, a halogen atom in the α- or β-position, a chloromethyl group in the α- or β-position, a linear or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl group in the α- or β-position, or an a straight or branched, saturated or unsaturated alkoxy or alkylthio group having 6 carbon atoms or an optionally substituted aryl or heteroaryl group and all other substituents are hydrogen.

...· ·..· .1.

According to another embodiment of the invention, in general formula (I), (I') and partial formulae (II')

R ⁷ represents a halogen atom in the α- or β-position, an α- or β-position straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkyl group having up to 10 carbon atoms, a straight or branched chain, saturated or unsaturated alkoxy group having up to 6 carbon atoms, or an optionally substituted aryl or heteroaryl group.

According to another embodiment of the invention, in general formula (I), (I') and partial formulae (II')

R ¹¹ is a nitroxy, hydroxy or mercapto group in the α- or β-position, a halogen atom in the α- or β-position, a chloromethyl group in the α- or β-position, a straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkyl group in the α- or β-position, a straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkoxy or alkylthio group in the α- or β-position, or an optionally substituted aryl or heteroaryl group in the α- or β-position,

R ¹⁵ is a halogen atom in the α- or β-position, a straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkyl group of up to 10 carbon atoms in the α- or β-position, which may be interrupted by one or more oxygen, sulfur, sulfoxide or sulfone groups or a group of the formula =NR ¹⁵ , where

R ¹⁵ ' represents a hydrogen atom, methyl, ethyl, propyl or isopropyl group and all other substituents represent a hydrogen atom.

...· ./. —* .^*

According to another embodiment of the invention, in general formula (I), (I') and partial formulae (II')

R ⁷ is an α- or β-halogen atom, an α- or β-position straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkyl group with up to 10 carbon atoms, a saturated or unsaturated alkoxy group with up to 6 carbon atoms or an optionally substituted aryl or heteroaryl group, R ¹¹ is an α- or β-position nitroxy, hydroxy or mercapto group, an α- or β-position halogen atom, an α- or β-position chloromethyl group, an α- or β-position straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkyl group with up to 10 carbon atoms, a straight or branched, saturated or unsaturated alkoxy or alkylthio group having 6 carbon atoms or an optionally substituted aryl or heteroaryl group, r ¹⁵ is a halogen atom in the α- or β-position, a straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkyl group having up to 10 carbon atoms in the α- or β-position, which may be interrupted by one or more oxygen, sulfur, sulfoxide or sulfone groups or a group of the formula =NR, where r ¹⁵ ' is a hydrogen atom, a methyl, ethyl, propyl or i-propyl group and all other substituents are hydrogen atoms.

··♦ · · · · ·· · · ·

..·· ·..· ./. — ·

In the case of the above embodiments of the compounds of the invention, in the general formula (I), (I') and in the partial formulae (II') preferably

R ⁷ represents a fluorine atom in the α- or β-position, a methyl, ethyl, propyl or isopropyl group in the α- or β-position, a trifluoromethyl group in the α- or β-position or a hydrogen atom,

R ¹¹ represents a nitroxy or hydroxy group in the α- or β-position, or a fluorine atom in the β-position, a chloromethyl group in the α- or β-position, a methyl group in the α- or β-position, a methoxy group in the α- or β-position, or a phenyl or 3-methylthien-2-yl group in the β-position or a hydrogen atom and

R ¹⁵ represents a fluorine atom in the α- or β-position, a methyl group in the α- or β-position, or a hydrogen atom.

According to the invention, the following compounds are preferred, and among these, the following compounds are particularly preferred:

14α,15α-methylene-oestra-1,3,5(10)-triene-3,16α-diol,

14β,15β-methylene-oestra-1,3,5(10)-triene-3,16a-diol,

14β,15β-methylene-oestra-1,3,5(10),8(9)-tetraene-3,16a-diol, oestra-1,3,5(10),8(9)-tetraene-3,16a-diol, oestra-1,3,5(10),8(14)-tetraene-3,16a-diol, oestra-1,3,5(10),6,8-pentaene-3,16a-diol, 7α-fluoro-oestra-1,3,5(10)-triene-3,16a-diol, Ιΐβ-methoxy-oestra-1,3,5(10)-triene-3,16a-diol, 7α-methyl-oestra-1,3,5(10)-triene-3,16a-diol, Ιΐβ-fluoro-oestra-1,3,5(10)-triene-3,16α-diol, 8α-oestra-1,3,5(10)-triene-3,16α-diol, oestra-1,3,5(10)-triene-2,3,16α-triol,

7·J. 7* 7*

17p-fluoro-oestra-l,3, 5(10)-triene-3,16a-diol, 18a-homo-oestra-l,3,5(10)-triene-3,16a-diol, 18a-homo-oestra-l,3,5(10),8(9)-tetraene-3,16a-diol, 18a-homo-14a,15a-methylene-oestra-l,3,5(10) -triene-3,16a-diol, 18-homo-14a,15a-methylene-oestra-l,3,5(10) ,8(9) -tetraene-3,16α-diol,

18a-homo-14a,15a-methylene-oestra-1,3,5(10), 6, 8-pentaene-3,16α-diol,

14α,15α-methylene-oestra-l,3,5(10)-triene-3,16β-άίο1, 14β,15β-ηθ1ί1έη-03ζ1η3-1,3,5(10)-triene-3,16β-diol, 14β, ^-methylene-oestra-l, 3,5(10),8(9) -tetraene-3,16β-άίο1, oestra-1,3,5(10),8(9)-tetraene-3,16β-άίο1, oestra-1,3,5(10),8(14)-tetraene-3,Ιδβ-diol, oestra-1,3,5(10),6,8-pentaene-3,16β-άϊο1, 7α-fluoro-oestra-1, 3,5(10) -triene-3,Ιδβ-diol, Ιΐβ-methoxy-estra-1, 3, 5(10)-triene-3,Ιδβ-diol, 7α-methyl-estra-1,3, 5(10)-triene-3,Ιδβ-diol, Ιΐβ-fluoro-estra-1,3,5(10)-triene-3,Ιδβ-diol, 8α-estra-1,3,5(10)-triene-3,Ιδβ-diol, estra-1,3,5(10)-triene-2,3,16α-triol, 17β-fluoro-estra-1,3, 5(10)-triene-3,Ιδβ-diol, 18α-homo-estra-1,3, 5(10)-triene-3,Ιδβ-diol, 18a-homo-oestra-l,3, 5(10),8(9)-tetraene-3,Ιδβ-diol, 18a-homo-14a,15a-methylene-oestra-l,3,5(10)-triene-3,Ιδβ-diol, 18a-homo-14a,15a-methylene-oestra-l, 3,5(10) , 8(9)-tetraene-3,Ιββ-diol, • ·· · · · ··« *·· í.' J. «.· -

18a-homo-14a, 15a-methylene-oestra-1,3,5(10),6,8-pentaene-3,Ιββdiol,

7a-ethyl-oestra-l,3,5(10)-triene-3,16a-diol, 7a-propyl-oestra-l,3,5(10)-triene-3,16a-diol, 7a-i-propyl-oestra-l,3, 5(10)-triene-3,16a-diol, 7a-i-propenyl-oestra-l,3, 5(10)-triene-3,16a-diol, 7a-phenyl-oestra-l,3,5(10)-triene-3,16a-diol, 7a-methoxy-oestra-l,3,5(10)-triene-3,16a-diol 7a-thiomethyl-oestra-l,3,5(10)-triene-3,Ιββ-diol, 7a-cyanomethyl-oestra-l,3,5(10)-triene-3,Ιββ-diol, 7β-ethyl-oestra-l,3,5(10)-triene-3,Ιββ-diol, 7β-propyl-oestra-l,3,5(10)-triene-3,Ιββ-diol, 7β-i-propyl-oestra-l,3,5(10)-triene-3,Ιββ-diol, 7β-1-ρΓορθηϊ1-03Ζ1Γ3-1, 3,5(10)-triene-3,Ιββ-diol, 7β-ίθηί1-03Ζ1Γ3-1,3,5(10)-triene-3,Ιββ-diol, 7β-Itιethoxy-oestra-l, 3,5(10)-triene-3,Ιββ-diol, 7β-ϋοπΐθϋ1-03ζ1η3-1,3, 5 (10)-triene-3, Ιββ-diol,

7β-οΪ3ηοΜθϋ1-03ζ1η3-1,3,5(10)-trié-3,Ιββ-diol,

7a-ethyl-oestra-1,3,5(10)-triene-3,Ιββ-diol,

7a-propyl-oestra-1,3,5(10)-triene-3,Ιββ-diol,

7a-i-propyl-oestra-1,3,5(10)-triene-3,Ιββ-diol,

7a-propenyl-oestra-1,3,5(10)-triene-3,Ιββ-diol, 7a-phenyl-oestra-1,3,5(10)-triene-3,Ιββ-diol, 7a-methoxy-oestra-1,3,5(10)-triene-3,Ιββ-diol,

7α-thiomethyl-estra-l,3,5(10)-triene-3,Ιββ-diol, 7α-cyanomethyl-estra-l, 3,5(10)-triene-3,Ιββ-diol, 7β-θϋ1-03ζίη3-1, 3,5 (10)-triene-3,Ιββ-diol, 7β- _Ρ Γορϋ-03Ζίη3-1, 3,5 (10)-triene-3, Ιββ-diol, 7β-i-propyl-estra-l,3,5(10)-triene-3,Ιββ-diol, 7β—i ^— propenyl-estra-1,3,5(10)-triene-3,Ιββ-diol, 7β-ίβηί1-03ΖίΓ3-1,3,5(10)-triene-3,Ιββ-diol, 7β-methoxy-oestra-l,3,5(10)-triene-3,Ιββ-diol, 7β ^— thioineethyl—oestra —1,3,5 (10) — triene—3,Ιββ-diol, 7β-cyanomethyl-oestra-l, 3,5(10)-triene-3,Ιββ-diol, 15α-methyl-oestra-l,3,5(10)-triene-3,16α-diol, 15α-ethyl-oestra-l,3,5(10)-triene-3,16α-diol, 15α-propyl-oestra-l,3,5(10)-triene-3,16α-diol, 15α-allyl-oestra-l,3,5(10)-triene-3,16α-diol, 15a-i-propyl-oestra-l,3,5(10)-triene-3,16a-diol, 15a-i-propenyl-oestra-l,3,5(10)-triene-3,16a-diol, 15a-methoxy-oestra-l,3,5(10)-triene-3,16a-diol, 15a-thiomethyl-oestra-l,3,5(10)-triene-3,16a-diol, 15a-methyl-oestra-l,3,5(10)-triene-3,Ιββ-diol, 15a-ethyl-oestra-l,3,5(10)-triene-3,Ιββ-diol, 15a-propyl-oestra-l,3,5(10)-triene-3,Ιββ-diol, 15a-allyl-oestra-1,3,5(10)-triene-3, Ιββ-diol, 15a-i-propyl-oestra-1,3,5(10)-triene-3,Ιββ-diol,

15a-i-propenyl-oestra-l,3,5 (10)-triene-3,Ιββ-diol, 15a-methoxy-oestra-l,3,5 (10)-triene-3,Ιββ-diol, 15a-thiomethyl-oestra-l,3,5 (10)-triene-3,Ιββ-diol, 15β-Inethyl-oestra-l, 3,5 (10) -triene-3,16a-diol, ^-ethyl-oestra-l, 3, 5 (10) -triene-3,16a-diol, ^-propyl-oestra-l, 3,5 (10) -triene-3,16a-diol, ^-allyl-oestra-l, 3, 5 (10) -triene-3,16a-diol, ^-i-propyl-oestra-l, 3, 5 (10) -triene-3,16a-diol, ^-i-propenyl-oestra-l, 3, 5(10) -triene-3,16a-diol, ^-methoxy-oestra-l, 3, 5 (10) -triene-3,16a-diol, 15β-thiomethyl-oestra-l, 3, 5(10) -triene-3,16a-diol, 15β-πΐ6ϋ1-03ζίΓ3-1, 3, 5 (10) -triene-3, Ιββ-diol, ^-ethyl-oestra-l, 3, 5 (10) -triene-3, Ιββ-diol, 15β-propyl-oestra-l,3,5(10)-triene-3,Ιββ-diol, Ιδβ-allyl-oestra-1,3,5(10)-triene-3,Ιββ-diol, 15β-i-propyl-oestra-l,3,5(10)-triene-3,Ιββ-diol, ^-i-propenyl-oestra-l, 3,5 (10) -triene-3,Ιββ-diol, ^-methoxy-oestra-l, 3, 5 (10) -triene-3,Ιββ-diol, 15β-thiomethyl-oestra-l,3,5(10)-triene-3,Ιββ-diol, 7α-trifluoromethyl-11β-fluoro-oestra-l, 3,5(10) -triene-í , 16α-diol,

7α pentafluoroethyl-lip-fluoro-oestra-1,3,5(10)-triene-3,16α-diol,

7a-ethyl-11β-fluoro-oestra-1,3,5(10)-triene-3,16a-diol, 7a-propyl-11β-fluoro-oestra-1,3,5(10)-triene-3,16a-diol, 7a-i-propyl-11β-fluoro-oestra-1,3,5(10)-triene-3,16a-diol, 7a-i-propenyl-11β-fluoro-oestra-1,3,5(10)-triene-3,16a-diol, 7a-phenyl-11β-fluoro-oestra-1,3,5(10)-triene-3,16a-diol, 7a-methoxy-11β-fluoro-oestra-1,3,5(10)-triene-3,16a-diol, 7a-thiomethyl-llp-fluoro-oestra-l,3,5(10)-triene-3, 16a-diol, 7a-cyanomethyl-llp-fluoro-oestra-l,3, 5(10)-triene-3,16a-diol, 7p-ethyl-llp-fluoro-oestra-l,3,5(10)-triene-3,16a-diol, 7p-propyl-Up-fluoro-oestra-l,3,5(10)-triene-3,16a-diol, 7p-i-propyl-llp-fluoro-oestra-l,3,5(10)-triene-3, 16a-diol, 7β-ϊ-ρΓορθηί1-11β-ίfluoro-oestra-l,3,5(10)-triene-3,16a-diol, 7p-phenyl-llp-fluoro-oestra-1, 3,5(10)-triene-3,16a-diol, 7β-methoxy-1β-fluoro-oestra-1,3,5(10)-triene-3,16a-diol, 7β-thiomethyl-1β-fluoro-oestra-1,3,5(10)-triene-3,16a-diol, 7β-cyanomethyl-1β-fluoro-oestra-1,3,5(10)-triene-3,16a-diol, 7α-ethyl-1β-fluoro-oestra-1,3,5(10)-triene-3,16β-diol, 7α-propyl-1β-fluoro- _oestra -1,3,5(10)-triene-3,16p-diol,

7α i-propyl-lip-fluoro-estra-l,3,5(10)-triene-3,Ιββ-diol, 7α-i-propenyl-l^-fluoro-estra-l, 3, 5 (10) -triene-3, Ιββ-diol, 7α-phenyl-l^-fluoro-estra-l,3,5(10)-triene-3, Ιββ-diol, 7α-methoxy-llβ-fluoro-estra-l,3,5(10)-triene-3,Ιββ-diol, 7α-thiomethyl-l^-fluoro-estra-l,3,5(10)-triene-3,Ιββ-diol, 7α-cyanomethyl-llβ-fluoro-estra-l, 3, 5(10) -triene-3, Ιββ-diol, 7β~θϋ1-11β-ίluoro-estra-1,3,5(10)-triene-3,Ιββ-diol, 7β-propyl-llβ-fl _U or-estra-l,3,5(10)-triene-3, Ιββ-diol, 7β-i-propyl-llβ-fl _U or-estra-l,3,5(10)-triene-3, Ιββ-diol, 7β-i-propenyl-llβ-fluoroestra-l,3, 5(10)-triene-3, Ιββ-diol, 7β-£θηϋ-11β-ί1ποΓ-03ζ1 _Γ 3-1,3, 5(10)-triene-3, Ιββ-diol, 7β-πΐθίοχί-11β-£1 _υ οΓ-03ζ^3-1,3,5 (10) -triene-3, Ιββ-diol, 7β-thio _I netyl-llβ-fluoro-estra-l, 3,5 (10) -triene-3, Ιββ-diol, 7β-cyanomethyl-llβ-fluoro-estra-l,3,5(10)-triene-3,Ιββ-diol, 15α-methyl-llβ-fluoro-estra-l, 3,5(10)-triene-3,Ιββ-diol, 15α-methyl-llβ-fluoro-estra-l, 3,5(10)-triene-3,16a-diol, 15α-ethyl-l^-fluoro-estra-l, 3,5 (10) -triene-3,16a-diol, 15α-propyl-l^-fluoro-estra-l, 3,5(10)-triene-3,16a-diol, 15α-allyl-llβ-fluoro-estra-l, 3,5(10)-triene-3,16a-diol, 15α-ί-ρ _Γ ορί1-11β-ίfluoro-estra-1,3,5 (10) -triene-3,16a-diol, 15α-i-propenyl-1^-fluoro-estra-l, 3,5 (10) -triene-3,16a-diol, 15α-methoxy-1^ _-fluoro -estra-l, 3,5 (10) -triene-3,16a-diol,

15α-ϋοιηθϋ1-11β-ί fluoro-estra-1,3,5(10)-triene-3,1δα-diol, 15α-methyl-11β-fluoro-estra-1,3,5(10)-triene-3,δβ-diol, 15α-ethyl-11β-fluoro-estra-1,3,5(10)-triene-3,δβ-diol, 15α-propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol, 15α-311ί1-11β-ί fluoro-estra-1,3,5(10)-triene-3,δβ-diol, 15α-i-propyl-11β-fluoro-estra-1,3,5(10)-triene-3,δβ-diol, 15α-ί-ρηορβηί1-11β-ίfluoro-estra-1,3,5(10)-triene-3,ίδβ-diol, 15α-methoxy-11β-fluoro-estra-1,3,5(10)-triene-3,ίδβ-diol, 15α-thiomethyl-11β-fluoro-estra-1,3,5(10)-triene-3,ίδβ-diol, 15β-methyl-11β-fluoro-estra-1,3,5(10)-triene-3,16a-diol, 15β-θίϋ-11β-ίfluoro-estra, 1,3,5(10) - triene-3,16a-diol, 15β-ρηορϋ-11β-ίfluoro-estra-1, 3,5(10) -triene-3,16a-diol, 15β-311ϋ-11β-ίfluoro-estra-1,3,5(10) -triene-3,16a-diol, 15β-ί-ρηορϊ1-1Ιβ-fluoro-estra-1,3,5(10)-triene-3,16a-diol, 15β-ί-ρηορθηϋ-11β-ί1ηοη-03Ζίη3-1,3,5(10)-triene-3,16a-diol, 15β-methoxy-11β-fluoro-estra-1,3,5(10)-triene-3,16a-diol, 15β-thiomethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16a-diol, 15β-methyl-11β-fluoro-estra-1,3,5(10)-triene-3, Ιδβ-diol, 15β-θίί1-11β-£luoro-estra-1,3,5(10)-triene-3,Ιδβ-diol, 15β-ρηορί1-11β-ίluoro-estra-1,3,5(10)-triene-3, Ιδβ-diol,

15β-311ί1-11β-ίfluoro-estra-1,3,5(10) -triene-3,Ιββ-diol, 15β-ί-ρηορί1-11β-ίfluoro-estra-1,3,5(10)-triene-3,16β-άϊο1, 15β-i-propenyl-11β-fluoro-estra-l, 3, 5(10)-triene-3,Ιδβ-diol, 15β-methoxy-11β-fluoro-estra-l,3,5(10)-triene-3,Ιδβ-diol, 15β-thiomethyl-11β-fluoro-estra-1,3, 5(10)-triene-3,Ιδβ-diol, 14α,15α-methylene-7α-phenyl-estra-l, 3,5(10)-triene-3,16a-diol, 14β, ^-methylene-7a-phenyl-oestra-l, 3,5(10) -triene-3,16a-diol, 14β,15β-methylene-7α-phenyl-oestra-l, 3,5(10),8(9) -tetraene-3,16a-diol,

7a-phenyloestra-1,3,5(10),8(9)-tetraene-3,16a-diol,

7a-phenyloestra-1,3,5(10),8(14)-tetraene-3,16a-diol,

7-phenyl-oestra-l,3,5(10),6,8-pentaene-3,16a-diol, l^-methoxy-7a-phenyl-oestra-l, 3,5 (10) -triene-3,16a-diol, llβ-fluoro-7α-phenyl-oestra-l,3,5(10)-triene-3,16a-diol, 7a-phenyl-8a-oestra-l,3,5(10)-triene-3,16a-diol, 7a-phenyl-oestra-l,3,5(10)-triene-2,3,16a-triol,

17β-fluoro-7a-phenyl-oestra-1,3,5(10)-triene-3,16a-diol, 18a-homo-7a-phenyl-oestra-1,3,5(10)-triene-3,16a-diol,

18a-homo-7a-phenyl-oestra-1,3,5(10), 8(9)-tetraene-3,16a-diol,

18a-homo-14a,15a-methylene-7a-phenyl-oestra-1,3,5(10)-triene28

-3,Ιδα-diol,

18a-homo-14a,15a-methylene-7a-phenyl-oestra-1, 3,5(10),8(9)-tetraene-3,16a-diol,

18a-homo-14a,15a-methylene-7-phenyl-oestra-1, 3,5(10),6,8-pentaene-3,16a-diol,

14a,15a-methylene-7a-phenyl-oestra-1,3,5(10)-triene-3,Ιδβ-diol,

14β,15β-methylene-7α-phenyl-oestra-l, 3,5(10) -triene-3,Ιδβ-diol, β,15β-methylene-7α-phenyl-oestra-1,3,5(10) ,8(9)-tetraene-3,Ιδβ-diol,

7a-phenyl-oestra-1,3,5(10),8(9)-tetraene-3,Ιδβ-diol,

7a-phenyl-oestra-1,3,5(10),8(14)-tetraene-3, Ιδβ-diol,

7-phenyl-oestra-1,3,5(10),6,8-pentaene-3,Ιδβ-diol, l^-methoxy-7aphenyl-oestra-1,3,5(10)-triene-3,Ιδβ-diol, llβ-fluoro-7α-phenyl-oestra-1,3,5(10)-triene-3,Ιδβ-diol,

7a-phenyl-8a-oestra-1,3,5(10)-triene-3,Ιδβ-diol,

7a-phenyl-oestra-1,3,5(10)-triene-2,3,16a-triol,

17β-ίfluoro-7α-phenyl-oestra-1,3,5(10)-triene-3, Ιδβ-diol,

18a-homo-7a-phenyl-oestra-1,3,5(10)-triene-3, Ιδβ-diol,

18a-homo-7α-phenyl-oestra-1,3,5(10),8(9)-tetraene-3,Ιδβ-diol,

18a-homo-14a,15a-methylene-7a-phenyl-oestra-1,3, 5(10)-triene-3,Ιδβ-diol,

18a-homo-14a,15a-methylene-7a-phenyl-oestra-1,3, 5(10),8(9)-tetraene-3,Ιδβ-diol,

18a-homo-14a,la-methylene-7-phenyl-oestra-l, 3, 5(10), 6,8-pentaene-3,Ιδβ-diol,

15a-methyl-7a-phenyl-oestra-1,3,5(10)-triene-3,Ιδα-diol,

15a-ethyl-7a-phenyl-oestra-1,3, 5(10)-triene-3,16a-diol,

15a-propyl-7a-phenyl-oestra-1, 3,5(10)-triene-3,16a-diol,

15a-allyl-7a-phenyl-oestra-1,3,5(10)-triene-3,16a-diol,

15a-i-propyl-7a-phenyl-oestra-1,3,5(10)-triene-3,16a-diol,

15a-1-propenyl-7a-phenyl-oestra-1,3,5(10)-triene-3,16a-diol,

15a-methoxy-7a-phenyloestra-1, 3,5(10)-triene-3,16a-diol,

15a-thiomethyl-7a-phenyl-oestra-1,3,5(10)-triene-3,16a-diol,

15a-methyl-7a-phenyl-oestra-1,3,5(10)-triene-3,Ιδβ-diol,

15a-ethyl-7a-phenyl-oestra-1,3,5(10)-triene-3,Ιδβ-diol,

15a-propyl-7a-phenyl-oestra-1,3,5(10)-triene-3,Ιδβ-diol,

15a-allyl-7a-phenyl-oestra-1,3,5(10)-triene-3, Ιδβ-diol,

15a-i-propyl-7a-phenyl-oestra-1,3,5(10)-triene-3, Ιδβ-diol,

15a-i-propenyl-7a-phenyl-oestra-1,3,5(10)-triene-3,Ιδβ-diol,

15a-methoxy-7a-phenyl-oestra-1,3,5(10)-triene-3,163-diol,

15α-thiomethyl-7α-phenyl-estra-1,3,5(10}-triene-3, Ιδβ-diol, 15β-Φβίί1-7α-ίβηϋ-03ζίΓ3-1,3,5(10)-triene-3,16α-diol, 15β-θϋ1-7α-ίοηί1-03ζίη3-1,3,5(10)-triene-3,16a-diol,

15p-propyl-7a-phenyl-oestra-l,3,5(10)-triene-3,16a-diol, 15β-allyl-7α-phenyl-oestra-l, 3,5(10)-triene-3,16a-diol, 15p-i-propyl-7a-phenyl-oestra-l,3,5(10)-triene-3,16a-diol, 15p-i-propenyl-7a-phenyl-oestra-l,3,5(10)-triene-3,16a-diol, 15p-methoxy-7a-phenyl-oestra-l,3,5(10)-triene-3,16a-diol, 15p-thiomethyl-7a-phenyl-oestra-l, 3,5(10)-triene-3,16a-diol, 15β-methyl-7α-phenyl-oestra-l, 3,5(10)-triene-3,Ιδβ-diol, 15β-ethyl-7α-phenyl-oestra-l, 3,5(10)-triene-3,Ιββ-diol, 15β-propyl-7α-phenyl-oestra-l,3,5(10)-triene-3,Ιββ-diol, ^-allyl-7α-phenyl-oestra-l, 3,5 (10) -triene-3,Ιββ-diol, 15β-i-propyl-7α-phenyl-oestra-l,3,5(10)-triene-3,Ιββ-diol, 15β-i-propenyl-7α-phenyl-oestra-l,3,5(10)-triene-3,Ιββ-diol, 15β-methoxy-7α-phenyl-oestra-l, 3,5(10)-triene-3, Ιββ-diol, 15β-thiomethyl-7α-phenyl-oestra-l, 3,5(10)-triene-3, Ιββ-diol, 15α-methyl-11β-fluoro-7α-phenyl-oestra-l,3,5(10)-triene-3,16α-diol,

15α-θ1ί1-11β-fluoro-7α-phenyl-oestra-1,3,5(10)-triene-3,16α-diol,

15α-ρηορϋ-11β-ί luoro-7a-phenyl-estra-1,3,5(10)-trien-3, 16a-diol,

15α-311ί1-11β-fluoro-7α-phenyl-oestra-1,3,5(10)-triene-3,16a31

-diol,

15a-1-propyl-11β-fluoro-7a-phenyl-oestra-1,3,5(10)-triene-3,16a-diol,

15a-1-propenyl-1-fluoro-7a-phenyl-oestra-1,3,5(10)-triene-3,16a-diol,

15a-methoxy-lip-fluoro-7a-phenyl-oestra-l, 3,5(10)-triene-3,16α-diol,

15a-thiomethyl-lip-fluoro-7a-phenyl-oestra-1, 3,5(10)-triene-3,16a-diol,

15a-methyl-lip-fluoro-7a-phenyl-oestra-1,3,5(10)-triene-3,16β-diol,

15a-ethyl-lip-fluoro-7a-phenyl-oestra-1,3, 5(10)-triene-3,16β-diol,

15α-propyl-11β-fluoro-7α-phenyl-oestra-1,3,5(10)-triene-3,16β-diol,

15a-allyl-1,4-fluoro-7a-phenyl-oestra-1,3,5(10)-triene-3,16β-diol,

15a-i-propyl-1^-fluoro-7a-phenyl-oestra-1,3,5(10)-triene-3,Ιββ-diol,

15α-ί-ρηορθηϋ-11β-ίluoro-7α-phenyl-estra-1,3,5(10)-triene-3,Ιββ-diol,

15a-methoxy-11β-fluoro-7a-phenyl-oestra-1,3,5(10)-triene-3,16β-diol,

15a-thiomethyl-11β-fluoro-7a-phenyl-oestra-1,3,5(10)-triene-3,Ιββ-diol, ··· · · · · ♦· . ...· ·..· .i.

15β-ωβ1ίΐ-ΐΐβ-fluoro-7α-phenyl-oestra-1, 3,5(10)-triene-3,16α-diol,

15p-ethyl-lip-fluoro-7a-phenyl-oestra-l, 3,5(10)-triene-3,16α-diol,

15p-propyl-lip-fluoro-7a-phenyl-oestra-1,3,5(10)-triene-3, 16α

-diol,

15β-allyl-11β-fluoro-7αa-phenyl-oestra-1, 3,5(10)-triene-3, 16α

-diol,

15β-i-propyl-1β-fluoro-7α-phenyl-oestra-1, 3,5(10)-triene-3,16α-diol,

15β-i-propenyl-1β-fluoro-7α-phenyl-oestra-1, 3,5(10)-triene-3,16α-diol,

15β-methoxy-11β-fluoro-7α-phenyl-oestra-1,3,5(10)-triene-3,16α

-diol,

15β-thioineethyl-1β-fluoro-7β-phenyl-oestra-1,3,5(10)-triene-3,16α-diol,

15β-methyl-11β-fluoro-7α-phenyl-oestra-1, 3,5(10)-triene-3, 16β-diol,

15β-θίϋ-11β-fluoro-7β-phenyl-oestra-1, 3,5(10)-triene-3, 16β-diol,

15β-propyl-11β-fluoro-7α-phenyl-oestra-1,3,5(10)-triene-3, 16β

-diol,

15β-311ί1-11β-ί1ηοη-7α3-ίθηί1-03ζίηη-1,3,5(10)-triene-3,16β

-diol,

15β-ί-ρΓορϋ-11β-ίluoro-7a-phenyl-estra-l, 3,5(10)-triene-3,Ιββ-diol,

15β-ί-ρ^ρθηί1-11β-ί 1υοη-7β-ί enyl-estra-1,3,5(10)-triene-3,Ιββ-diol,

15β-ιηθ1οχί-11β-εfluoro-7α-phenyl-oestra-1,3,5(10)-triene-3,16β

-diol,

15β-1ίοιηθΡϊ1-11β-ί1οοΓ-7α-ίθηί1-03ζ1Γ3-1,3, 5 (10)-triene-3,16βdiol,

11β—[2-(3-methylthien)-yl]-oestra-1,3,5(10)-triene-3,16a-diol

11β—[2-(3-Methylthien)-yl]-oestra-1,3,5(10)-triene-3,Ιββ-diol

13a-oestra-1,3,5(10)-triene-3,16a-diol,

13a-oestra-1,3,5(10)-triene-3,Ιββ-diol,

14β-03ζ1Γ3-1,3,5(10)-triene-3,16a-diol,

14β-03ζ1η3-1,3,5(10)-triene-3,Ιββ-diol,

Ιΐβ-methylestradiol-1,3,5(10)-triene-3,16a-diol,

Ιΐβ-methyloestra-l,3,5(10)-triene-3,Ιββ-diol, llβ-methyl-18a-homoestra-1,3,5(10)-triene-3, Ιβα-diol, llβ-methyl-18a-homoestra-1,3,5(10)-triene-3,Ιββ-diol,

Ιΐβ-ethylestradiol-1,3,5(10)-triene-3,16a-diol,

Ιΐβ-ethylestra-l,3,5(10)-triene-3,Ιββ-diol, llβ-ethyl-18α-homoestra-l,3,5(10)-triene-3,16α-diol, lp-ethyl-18α-homoestra-l,3,5(10)-triene-3,Ιδβ-diol,

Ιΐβ-vinyl estra-1,3,5(10}-triene-3, 16a-diol,

Ιΐβ-vinyloestra-l,3,5(10)-triene-3, Ιδβ-diol, llβ-vinyl-18a-homoestra-l,3,5(10)-triene-3,16a-diol, llβ-vinyl-18a-homoestra-l,3,5(10)-triene-3, Ιδβ-diol, Ιΐβ-ethynylestra-1,3,5(10)-triene-3,16a-diol,

Ιΐβ-ethynyl estra-l,3,5(10)-triene-3,Ιδβ-diol, llβ-ethynyl-18a-homoestra-l,3,5(10)-triene-3, 16a-diol, Ιΐβ-ethynyl-18a-homoestra-l,3,5(10)-triene-3, Ιδβ-diol, 9a-Methyloestra-1,3,5(10)-triene-3,16a-diol, 9a-methyloestra-1,3,5(10)-triene-3, Ιδβ-diol, 9a-methyl-18a-homoestra-1,3,5(10)-triene-3,16a-diol, 9α-methyl-18α-homoestra-1,3,5(10)-triene-3,Ιδβ-diol, 7a-methyl-18a-homoestra-l,3,5(10)-triene-3,16a-diol, 7a-methyl-18a-homoestra-l,3,5(10)-triene-3, Ιδβ-diol, 7a-ethyl-18a-homoestra-l,3,5(10)-triene-3,16a-diol, 7α-ethyl-18α-homoestra-1,3,5(10)-triene-3,Ιδβ-diol, 7α,Ιΐβ-dimethyloestra-1,3,5(10)-triene-3,16α-diol,

7α,Ιΐβ-dimethyloestra-1,3,5(10)-triene-3,Ιδβ-diol,

7α,11β-dimethyl-18α-homoestra-1, 3,5(10)-triene-3,16α-diol

7α, 11β-dimethyl-18α-hoinoestra-1, 3,5(10)-triene-3,16α-diol

16β-ethynyl-18α-homoestra-1,3,5(10)-triene-3, 16α-diol,

16α-ethynyl-18α-homoestra-1,3,5(10)-triene-3,Ιδβ-diol,

7α-methyl-16β-ethynyl estra-1,3,5(10)-triene-3,1δα-diol,

7α-methyl-16α-ethynylestra-1,3,5(10)-triene-3,Ιδβ-diol,

7α-methyl-16β-ethynyl-18α-homoestra-1,3,5(10)-triene-3,16α-diol

7α-methyl-16α-ethynyl-18α-homoestra-l,3,5(10)-triene-3,16β-diol, llβ-methyl-16β-ethynylestra-l,3,5(10)-triene-3,16a-diol, llβ-methyl-16α-ethynylestra-l,3,5(10)-triene-3, Ιδβ-diol,

Ιΐβ-methyl-16β-ethynyl-18a-homoestra-1,3,5(10)-triene-3,16α-diol, llβ-methyl-16α-ethynyl-18a-homoestra-1,3,5(10)-triene-3,16β-diol.

Another object of the invention is the use of the structural element of partial formula (II) as a component of the overall structure of compounds whose effects are divided in favor of the estrogenic effect on the bones, compared to the effect on the uterus.

The substituents on carbon atoms 7, 8, 9, 11, 13, 14, 15 and 17 can always be in the α- or β-position; the dashed lines in rings B, C and D represent one or more double bonds between the corresponding carbon atoms.

According to the invention, preferred partial structures of general formula (II') are those in which

R ¹ ' - R ¹⁷ ' independently have the following meanings:

R ¹ ' is a halogen atom, a hydroxy, methyl, trifluoromethyl, methoxy, ethoxy group or a hydrogen atom,

R ² ' halogen atom, hydroxy, up to 6 carbon atoms straight or branched chain, saturated or unsaturated alkoxy group or hydrogen atom, R ⁴ ' halogen atom, up to 10 carbon atoms straight or branched chain, saturated or unsaturated alkyl group, trifluoromethyl or pentafluoroethyl group, up to 6 carbon atoms straight or branched chain, saturated or unsaturated alkoxy group or hydrogen atom, R ⁴ ' halogen atom, up to 10 carbon atoms straight or branched chain, saturated or unsaturated alkyl group, trifluoromethyl or pentafluoroethyl group, up to 6 carbon atoms straight or branched chain, saturated or unsaturated alkoxy group or hydrogen atom, R ⁴ ' halogen atom, up to 6 carbon atoms straight or branched chain, saturated or unsaturated alkoxy group or hydrogen atom a straight or branched chain, saturated or unsaturated alkyl group having up to 10 carbon atoms, a trifluoromethyl or pentafluoroethyl group, a straight or branched chain, saturated or unsaturated alkoxy group having up to 6 carbon atoms or a hydrogen atom, R ⁷ 'is a halogen atom in the a- or β-position, a straight or branched chain, saturated or unsaturated alkyl group having up to 10 carbon atoms in the a- or β-position, a straight or branched chain, saturated or unsaturated alkoxy group having up to 6 carbon atoms, optionally substituted aryl or heteroaryl group or a hydrogen atom, R ⁸ 'is a hydrogen atom in the a- or β-position, a cyano group in the a- or β-position or a straight or branched chain, saturated or unsaturated alkyl group having up to 10 carbon atoms in the a- or β-position, optionally partially or fully fluorinated,

AX 17*

R is a hydrogen atom in the α- or β-position, a methyl, ethyl, trifluoromethyl or pentafluoroethyl group in the α- or β-position,

R is a nitroxy, hydroxy or mercapto group in the α- or β-position, a halogen atom in the α- or β-position, a chloromethyl group in the α- or β-position, a straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkyl group in the α- or β-position, having up to 10 carbon atoms, a straight or branched chain, saturated or unsaturated alkoxy or alkylthio group having up to 6 carbon atoms, an optionally substituted aryl or heteroaryl group or a hydrogen atom,

R ¹³ ' is a methyl, ethyl, trifluoromethyl or pentafluoroethyl group in the α- or β-position and

R is a straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkyl group of up to 10 carbon atoms in the α or β position or a hydrogen atom in the α or β position, and

R ¹⁵ is a halogen atom in the α- or β-position, a straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkyl group of up to 10 carbon atoms, which may be interrupted by one or more oxygen, sulfur, sulfoxide or sulfone groups or a group of the formula =NR ¹⁵ ', where

R ¹⁵ 'is hydrogen, methyl, ethyl, propyl or i-propyl or hydrogen, or

R ¹⁴ ' and R ¹⁵ ' together are a 14α,15a-methylene or 14p-15P-methylene group optionally substituted with 1 or 2 halogen atoms, R ¹⁶ ' is a straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkyl group in the α- or β-position, up to 10 carbon atoms, trifluoromethyl or pentafluoroethyl group, cyanomethyl group or a hydrogen atom in the α- or β-position, R ¹⁷ ' is a halogen atom in the α- or β-position, a straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkyl group in the α- or β-position, hydrogen atom or hydroxyl group, and in the formula the dotted line in the B, C and D rings optionally represents one or more double bonds, while the wavy line indicates that the given substituent is in the α- or β-position.

The invention describes novel compounds with selective estrogenic activity which show differences in binding to estrogen receptor preparations from rat prostate and rat uterus in vitro and advantageously show differences in their effects on bone and uterus in vivo. In a wide dose range, the compounds have a bone-protecting effect without stimulating the uterus. In the same dose range, their effects on the liver are minor. In addition, the compounds have estrogenic effects on the circulatory system and brain functions.

The invention also relates to pharmaceutical compositions which contain at least one compound of the general formula (I) or a physiologically acceptable salt thereof formed with organic or inorganic acids, and to the use of these compounds for the preparation of medicaments, in particular for the indications described below.

The compounds can be administered orally or parenterally for the following indications.

The novel selective estrogens of the invention can be used as the sole component in pharmaceutical compositions or can be combined, in particular with antiestrogens or gestagens. It is particularly advantageous to combine selective estrogens with ERα selective antiestrogens or with antiestrogens that have a selective peripheral effect, i.e. do not cross from the blood into the brain.

The compounds and pharmaceutical compositions containing them are particularly suitable for the treatment of peri- and postmenopausal complaints, such as in particular hot flashes, sleep disorders, irritability, mood swings, incontinence, vaginal atrophy, mood disorders attributable to hormone deficiency. The compounds are suitable for use in hormone replacement therapy and for the treatment of hormone deficiency disorders in the case of ovarian dysfunction caused by surgical, pharmacological or other interventions. This also includes the tendency to lose bone mass in women after menopause, after hysterectomy or after treatment with LHRH agonists or antagonists.

The compounds are suitable for the alleviation of andropause and menopause symptoms (i.e. for use in hormone replacement therapy for men and women), both for prevention and treatment, as well as for the treatment of diseases associated with dysmenorrhea and for the treatment of acne.

The compounds can also be used for the following therapeutic purposes: prevention of bone loss and osteoporosis caused by hormone deficiency, prevention of cardiovascular diseases, especially vascular diseases such as atherosclerosis, inhibition of arterial smooth muscle cell proliferation, treatment of primary pulmonary hypertension, prevention of neurodegenerative diseases caused by hormone deficiency (such as Alzheimer's disease) and influencing memory and learning ability based on hormone deficiency.

The compounds can also be used for the treatment of inflammatory diseases of the immune system (especially autoimmune diseases), e.g. rheumatoid arthritis.

The compounds can also be used to treat male sterility disorders and prostate diseases.

The compounds can also be used in combination with natural vitamin D3 or calcitriol analogues to influence bone formation, or as adjunctive therapy to therapies that cause bone loss (e.g. glucocorticoid therapy, chemotherapy).

Finally, the compounds of general formula (I) can also be used in combination with progesterone receptor antagonists, particularly in hormone replacement therapy and for the treatment of gynecological disorders.

EP-A 346 014 describes a pharmaceutical composition comprising an estrogen and a pure antiestrogen for simultaneous, sequential or independent administration in the selective estrogen therapy of peri- and postmenopausal conditions. The amount of a compound of the general formula (I) to be administered varies within wide limits and includes all effective amounts. The amount of compound administered may be between 0.01 μg/kg/day and 10 mg/kg/day, preferably between 0.04 μg/kg/day and 1 mg/kg body weight/day, depending on the condition to be treated and the route of administration.

In humans, this corresponds to a dose of 0.8 μg/day - 800 mg/day - preferably 3.2 μg/day - 80 mg/day.

A dosage unit according to the invention contains 1.6 μg to 200 mg of one or more compounds of general formula (I).

The compounds according to the invention and their acid addition salts are suitable for the preparation of pharmaceutical mixtures and preparations. The pharmaceutical preparations or medicaments contain one or more compounds or acid addition salts according to the invention as active ingredients, optionally together with other pharmacologically or medicinally active substances. The medicament is prepared in a known manner; known and customary pharmaceutical excipients and other customary carriers and diluents can be used.

Such carriers and auxiliaries may include, for example, those recommended or given in the following literature for use in pharmaceutical, cosmetic and similar applications: Ullman: Encyclopedia of Technical Chemistry, Volume 4, pp. 1-39; H.v. Czetsch-Lindenwald:

...............

··· · · · · ··· ··· • · · · · · ······ ·

J.Pharm.- Sci. 52, p. 918, 1963; Pharm.Ind. 2. füzet, p. 72., 1961; H.P. Fiedler: Lexikon dér Hilfsstoffe für Pharmazie, Kosmetik und angrenzende Gebiete, Cantor KG, Aulendorf in Württemberg, 1971. The compounds can be administered orally or parenterally, e.g. intraperitoneally, i.m., s.c. or percutaneously. The compounds can also be implanted into the tissue.

For oral administration, capsules, pills, tablets, dragees, etc. may be considered. The dosage units may contain, in addition to the active ingredient, pharmaceutically acceptable excipients (e.g. starch, sugar, sorbitol, gelatin, lubricants, silicic acid, talc, etc.).

For parenteral administration, the active ingredients can be dissolved or suspended in a physiologically acceptable diluent. Oils are very often used as diluents, optionally with the addition of a solubilizer, a surfactant or a suspending agent or emulsifier. Examples of oils used are olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil.

The compounds may also be used as depot injections or implant formulations, which may be formulated to provide delayed release of the active ingredient.

The implants may contain, for example, biodegradable polymers or synthetic silicones, such as silicone rubber, as inert materials. The active ingredients may also be incorporated into a patch for percutaneous application.

For the production and local application of intravaginal (e.g. vaginal ring) systems containing active ingredients of general formula (I) or intrauterine (e.g. pessary, spiral, intrauterine devices, MirenaV) systems for local administration, various polymers can be used, such as silicone polymers, ethylene-vinyl acetate, polyethylene or polypropylene.

To improve the bioavailability of the active ingredient, the compounds can also be formulated in cyclodextrin clathrate form. For this purpose, the compounds can be converted with α-, β- or γ-cyclodextrin or their derivatives /PCT/EP95/02656/.

The compounds of formula (I) according to the invention can also be encapsulated in liposomes.

Methods

Estrogen receptor binding assays

The binding affinity of the new selective estrogens was determined by competition experiments with estrogen receptors prepared from rat prostate and rat uterus using 3H-estradiol as ligand. The estrogen receptor assay was performed with prostate cytosol as described by Testas et al. /Endocrinology 109, 1287-1289, 1981/.

Rat uterine cytosol preparation was performed essentially as described by Stack et al./Endocrinology 117, 2024-2032, 1985/, with modifications according to Fuhrmann et al. /Contraception 51, 45-52, 1995/.

The substances described in the context of the disclosure of the invention show a higher binding affinity for estrogen receptors derived from rat prostate than for those prepared from rat uterus. In this regard, it should be assumed that in rat prostate, ΕΕβ dominates over ERα, while in rat uterus, ERα dominates over ΕΕβ. Table 1 shows that the ratio of prostate and uterine receptor binding is qualitatively the same as the ratio of the relative binding affinity /RBA/ to human ERβ and rat ERα /Kuiper et al.: Endocrinology 138, 863-870, 1996/.

In vivo studies have also confirmed the predictability of the results of the “prostate ER - uterus ER” test system with regard to tissue selective effects. Substances that preferentially bind prostate ER in vitro are divided in terms of their effects on bone and uterus, with the effect on bone dominating.

Bone studies: Month-old female rats were ovariectomized and treated with the test compound once daily for 28 days immediately after surgery. This administration was s.c., with a peanut oil/ethanol mixture. The animals were sacrificed the day after the last administration and the tibia and uterus were removed. The uterus was weighed, fixed and processed for histological examination. Bone density was determined on ex vivo prepared long bones using QCT (quantitative computed tomography). Measurements were made at a distance of 4-6 mm from the proximal end of the tibia.

As a result of the removal of the ovaries, the density of the trabecular bone in the measured range decreases from about 400 mg Ca ²⁺ /cm ³ to about 300 mg Ca ²⁺ /cm ³ . Treatment with a compound of the general formula (I) according to the invention inhibits or prevents the decrease in bone density. The bone density was measured on the proximal tibia.

Table 2 shows the data for the following compounds for use in the invention: oestra-1, 3,5/10/-triene-3,16a-diol, the compound of Examples 3, 4, 9 and 10, 7β-ethyloestra-1,3,5/10/-triene-3, Ιδβ-diol, 7α-ethyloestra-1,3,5/10/,7-triene-3,Ιδβ-diol, 7β-03ζίτ3-1,3,5/10/,7-tetraene-3,Ιδβ-diol, 7α-phenyloestra-1,3,5/10/-triene-3, Ιδβ-diol, 7β-ίenyloestra-1,3,5/10/-triene-3, Ιδα-diol and 7β-ethyl-oestra-1,3,5/10/-triene-3, Ιδα-diol.

They show higher binding affinity for the estrogen receptor from rat prostate than for the estrogen receptor from rat uterus; in the case of oestra-1,3,5/10/triene-3,Ιδα-diol

ER/RBA/patfcani prostate ⁼ 50 ÓS

ER/RBA/rat uterus ~ 9.

In vivo, this is expressed in highly variable amounts of oestra-1,3,5/10/-triene-3,Ιδαdiol, which induce 50% bone protection (3μg/animal) and 50% uterine stimulation (30μg/animal) relative to the bone mass loss measured in untreated ovariectomized female rats 28 days after ovariectomy compared to intact animals that underwent sham surgery.

The effect of the estrogens of the invention on the circulatory system was determined in the ApoE-knockout mouse model /Elhage et al.: Arterioscl., Thrombosis and Vascular Biol. 17, 2679-2684, 1997/.

To detect the effect of estrogens on brain function, we used the mRNA expression of the oxytocin receptor as a surrogate parameter /Hrabovszky et al. : Endocrinol. 1339, 2600-2604, 1998/. Ovariectomized rats were treated with the test compound or vehicle for 7 days /administration: sc or per os, six times a day/. On the 7th day after the first administration, the animals were decapitated, the uterine weight was determined and the oxytocin receptor mRNA level was examined by in situ hybridization, on appropriate sections prepared from the brain. The ED ₅₀ values were determined for stimulation of uterine growth and oxytocin receptor mRNA.

A further possibility for investigating the difference in estrogenic effects of the compounds of the invention is to determine what effects occur after a single administration of the substances in the rat, in terms of 5HT2a receptor, serotonin transporter protein and mRNA levels in ERp-rich brain areas. The effect on LH secretion is measured in comparison to the effect on serotonin receptor and transporter expression. Substances showing higher binding to the rat prostate are more potent in terms of increasing serotonin receptor and transporter expression - compared to rat uterine estrogen receptors - than in terms of positively influencing LH secretion. Serotonin receptor and transporter density is determined on brain sections using radioactive ligands, and the corresponding mRNA is determined using in situ hybridization. The methodology is described in the literature /Fink et al.: Nature 383

306, 1996; Sumner et al.: Molecular

Brain Research, 1999/.

Preparation of the compounds of the invention

There are primarily two generally applicable strategies available for the preparation of the compounds of the invention, i.e. modified/substituted derivatives of oestra-1,3,5/10/triene-3,16ζ-diols.

On the one hand, 3,16-protected derivatives of estra-1,3,5/10/triene-3,Ιδζ-diols, but in some cases, free diols can also be modified at certain positions of the skeleton.

A typical example of this is the 11-nitrate esters. The starting point is the well-known oestra-1,3,5/10/triene-3, 16β-όϊο1, which is first oxidized at the C(9), C(ll) position /Sykes et al.: Tetrahedron Letters 3393, 1971/. Reductive removal of the C(9) benzyl hydroxy group already provides the 11-nitrate ester of oestra-1,3,5/10/triene-3,11β,16β-triol protected in the diacetate form. After inversion of the C(16)-hydroxy group, saponification gives oestra-1,3,5/10/triene-3,16α-diol. However, this outlined synthesis route can also be carried out in the opposite direction, if we use oestra-1,3,5/10/triene-3,16a-diol as the starting material. Thus, we first obtain the 11-nitrate esters of the 16a-hydroxy-series. Further intermediate compounds, such as estra-1,3,5 (10) triene-3, 9,11β, Ιδξ-tetraol, can only be prepared after the cleavage of the C(3), C(16) protecting groups.

are available for inspection with properly modified original

-analogs, which are a large number, in a known manner, of but not limited to synthetic e

Within the framework of procedures that

Typical substitution patterns can be used to show the 9-membered estrogen skeleton, e.g. C(1): J.Chem.Soc. 2915, 1968 C(7): Steroids 54, 71, 1989

C(8a): Tetrahedron Letters 743, as follows:

1991

C(8p) :

Tetrahedron Letters 1763, 1964;

Tetrahedron 25,

4011,

1969;

J. Org. Chem.

J.Steroid

1977;

J. Org. Chem.

35, 468, 1970 ο _Ί 549, 1988; Tetrahedron 33,

Biochem. 3J-,

60, 5316, 1995

609,

C(9) :

C(15)

DE-OS 2035879; J.Chem.Soc. Perk.1 _: j.Chem.Soc.Perk.1, 1269, 1996 , 2095, 1973

C(13a): Mendeleev Common. 13V 199 ⁴

C(14B): Z.Chem. 23, 410, 1983, . , the transfer of the rim to C(16). The addition of the oxygen function allows for a flexible approach ^{to the} synthesis of the compounds of the invention. However, the _former can also be used.

During the use of some substituents, mostly the 7α-isomers are formed. These are mixtures of ίβ-isomers, which can be separated into the individual isomers by a method known to the skilled person, such as chromatography.

₈ a-Estra-1,3,5/10/trien-17-one

C (3)-methyl ^_ ether /Bull.Soc.Chim.Fr. 561, 1967/ detailed, given. After the description of the exemplary conversion of the ketone to the sulfonyl hydrazone /in the simplest case by reaction with phenyl sulfonyl hydrazide/ the cleavage reaction of the C(16)-C(17) olefin bond follows /Z.Chem. 10, 221-222, 1970; Liebig's Annals of Chemistry 1973-1981, 1981/, during which hypobromide is added in a region-/stereo-controlled manner. Reductive dehalogenation and removal of the C(3) protecting group provide the Ιββ-alcohol, which can be converted to the 16α-epimer in a known manner.

A further alternative to introducing the -OH group at C16 is the hydroboration of the 16(17)-double bond with spherically oriented boranes. This reaction is known to lead to 16-oxygenated products (Indian J.Chem. 9, 287-288, 1971). Accordingly, the reaction of 3-methoxy-oestra-1,3,5/10/,16-tetraene and 3methoxy-18a-homoestra-1,3,5/10/,16-tetraene with 9-borabicyclo-/3.3.1/nonane, after oxidation with an alkaline hydrogen peroxide solution, leads to 16a-hydroxyoestratrienes. A small amount of epimeric 16β-hydroxysteroid is also formed during this reaction. After cleavage of the 3-methoxy group, estra-1,3,5/10/triene-3,16αdiols are obtained.

After inversion of the configuration at C16, e.g. by the Mitsunobu reaction /Synthesis 1, 1980/, we again obtain the φ-hydroxyestratrienes.

The widespread application of the synthesis route outlined above can be demonstrated by further examples, such as in the case of 3-methoxy-7αmethyl-oestra-1,3,5/10/trien-17-one /Helv.Chim.Acta 281, 1967/ or in the case of 1,3-dimethoxy-oestra-1,3,5/10/trien-17-one /J.Org.Chem. 32, 4078, 1967/.

...............

• · · f · · ··· ·· ·· · ··♦

The preparation of the C(16)-C(17)-olefin intermediate is not limited to the arylsulfonylhydrazone method. In cases where the substituents on the steroid skeleton cannot be subjected to the basic reaction conditions of olefination, other methods can be considered, in particular the conversion of the C(17) ketone to vinyl iodide (Tetrahedron 147, 1988) or to enol triflate (Tetrahedron Letters 4821, 1984) with subsequent reactions.

If we choose the synthetic route leading through C(16)-keto derivatives, which can be converted to C(16)a-alcohols by 0(16)β- or inversion, the possibility of C(17)-C(16) keto-transposition can also be chosen. A specific example of this is also presented in J.Chem. Soc. Perk.l, 1350, 1976.

Fluorine atoms can be introduced onto carbon atoms 15 and 17 of the 16-hydroxy-estratrienes according to the invention by hydroboration of 15-fluoro-estra-1,3,5/10/,16-tetraenes or 17-fluoro-estra-1,3,5/10/,16-tetraenes with spherically defined boranes and alkaline hydrogen peroxide. The 15-fluoro-estra-1,3,5/10/, 16-tetraenes can be prepared, for example, from 15-hydroxy-estra-1,3,5/10/-triene-17-tin. First, the secondary -OH group on carbon atom 15 must be replaced by a fluorine atom. This can be done, for example, by 15α-hydroxyestrone, which can be prepared according to US 3 375 174, is converted into 15β-ί1ηοΓ-estrone in a known manner, by reaction with diethylaminosulfur trifluoride, or the corresponding 15α-mesylate is reacted with tetra-n-butylammonium trifluoride /J.Chem.Res.(M) 4728-4755, 1979/. The 15β-ίfluoro-estra-1,3,5/10/-trien-17-ones thus prepared are converted into tosylhydrazones. Bamford-Stevens reaction of 15-fluorinated tosylhydrazones for the introduction of the 16-OH group ··· · · · ·♦· *··

...· ·..· .1, necessary to produce 15-fluoro-oestra-1,3,5/10/,16-tetraenes. The 17-fluoro-oestra-1,3,5/10/,16-tetraenes required for the preparation of 17-fluorinated 16-OH-oestratrienes can be synthesized by known methods. The corresponding ketones can be converted into geminal difluoride by reaction with sulfur tetrafluoride /J.Org.Chem. 36, 818-820, 1971/ or by reaction with dialkylaminosulfur trifluoride - e.g. diethylaminosulfur trifluoride - /US 3 976 691/. From these, hydrogen fluoride can be eliminated by heating with geminal alumina in an inert solvent /US 3 413 321/, and thus fluoroolefins are obtained. These fluoroolefins can also be prepared directly from ketones by reacting them with diethylaminosulfur trifluoride in a polar solvent with the addition of strong acids (e.g. fuming sulfuric acid) /US 4,212,815/. 17-fluoroestra-1,3,5/10/,16-tetraen-3-ol according to US 3,413,321 can be converted into 17β-fluoroestra-1,3,5/10/-triene-3,16a-diol by reaction with spherically defined borane and subsequent oxidation with alkaline hydrogen peroxide.

As a further variant, the introduction of double bonds may be useful. In addition to their recognized medicinal importance as selective estrogens according to the invention, these unsaturated derivatives are valuable intermediates for the preparation of new 16-OH-estra-1,3,5/10/-trienes. A method for the introduction of a 9/11/-double bond is described below.

Steroids with an aromatic A ring are converted to 9a-OH steroids with dimethyldioxirane; dehydration of these leads to oestra-1,3,5/10/,9/ll/-tetraenes /Tetrahedron 50, 10709-10720/. The reaction of in situ prepared dimethyldioxirane with 18α52 • ·· · · * ·«· ··« • · · · · · ··* ·« **· homooestra-1,3,5/10/-triene-3,16a-diyl diacetate gives the corresponding 9a-OH compound. Dehydration of this tertiary alcohol leads to 18α-homoestra-1,3,5/10/, 9/ll/-tetraene-3,16αdiyl diacetate. After saponification, 18α-homoestra1,3,5/10/-triene-3,16α-diol is obtained.

The compounds of formula (I) according to the invention are prepared as described in the examples. Further compounds of formula (I) can be prepared by an analogous procedure using reagents homologous to those described in the examples. The etherification and/or esterification of the free -OH groups is carried out by methods known to the person skilled in the art.

Example 1

8a-Estra-1,3,5/10/-triene-3, 16β-άϊο1

3-Methoxy-8a-oestra-1,3,5/10/-trien-17-one-17-phenylsulfonylhydrazone

5.68 g (20 mmol) of 3-methoxy-8a-oestra-1,3,5/10/-trien-17-one and 4.30 g (25 mmol) of benzenesulfonic acid hydrazide are suspended in 70 ml of ethanol and 3 drops of cc. sulfuric acid are added to the suspension, then the reaction is carried out for 3 hours at a bath temperature of 80-90°C with vigorous stirring. After the reaction mixture has cooled, the precipitated product is filtered off with suction, washed with a little cold ethanol and the hydrazone is dried in vacuo. 8.10 g (92%) of product are obtained; m.p. 183-185°C.

3-Methoxy-8a-oestra-1,3,5/10/,16-tetraene

8.10 g /18.5 mmol/ of the hydrazone described above in 140 ml of dry ether in an ice bath with the exclusion of moisture /argon atmosphere/

Cool to 0°C and add dropwise 30 ml of ethereal methyl lithium (57 mmol). After the addition is complete, the cooling bath is removed and the mixture is stirred at room temperature for 3 hours. For work-up, cool to 0°C and carefully add 30 ml of saturated aqueous ammonium chloride solution with vigorous stirring. Acetic acid is added to this mixture, the organic phase is washed with water/brine and dried over sodium sulfate. The crude product is chromatographed on silica gel (hexane:ethyl acetate 95:5). 3.60 g (72%) of product are obtained.

17a-Bromo-3-methoxy-8a-estra-1,3,5/10/-trien-16β-ol

75 ml of dimethyl sulfoxide are added to 3.40 g (12.67 mmol) of olefin, then 5 ml of water are added to the solution and 2.80 g (15.75 mmol) of N-bromosuccinimide are added all at once with intensive stirring. For the work-up, the mixture is left to react at room temperature for 4.5 hours, then poured into water, extracted with 300 ml of ethyl acetate, the organic phase is washed first with water and then with brine and dried over sodium sulfate. The crude product is chromatographed on silica gel (toluene/acetone 9:1). Yield 3.50 g (75%) in the form of an oil.

3-Methoxy-8a-estra-1,3,5/10/-trien-16β-ol

3.50 g (9.60 mmol) of 17a-bromo-3-methoxy-8a-estra-1,3,5/10/-trien-16p-ol, 3.50 g (12.03 mmol) of tributyltin hydride and 50 mg of azobis(isobutyro)nitrile are dissolved in 30 ml of dry tetrahydrofuran and the solution is refluxed under argon atmosphere for 2 hours with stirring. For the work-up, the solution is allowed to cool, concentrated in vacuo in a rotary evaporator and the residue is taken up in 300 ml of ethyl acetate. The organic phase is washed with aqueous hydrochloric acid, water and brine, then dried over sodium sulfate. The residue is chromatographed on silica gel (dichloromethane/ethyl acetate 9:1). Yield 2.70 g (98%).

α-Estra-1,3,5/10/-triene-3,16β-diol (1)

1.10 g (3.80 mmol) of methyl ether in 35 ml of diisobutylaluminum solution in toluene (1.2 molar solution) was refluxed for 4 hours under argon atmosphere in the absence of moisture. The reaction mixture was then cooled in an ice bath and an ethyl acetate/water mixture was carefully added while stirring. The precipitate formed was separated by filtration, washed thoroughly with ethyl acetate and the organic phase was concentrated in vacuo. The crude product was recrystallized from acetone/hexane. Yield 679 mg (65%), mp 181-182°C, /a/ _D = +13.6° /c=0.52, methanol/.

Example 2

8a-Estra-1,3,5/10/-triene-3,16a-diol

3-Methoxy-8a-estra-1,3,5/10/-trien-16a-ol

To a mixture of 1.50 g (5.24 mmol) of 3-methoxy-8a-oestra-l, 3, 5/10/-trien-16β-ol, 2.06 g (7.85 mmol) of triphenylphosphine and 0.3 ml of formic acid in 10 ml of dry toluene, 1.22 ml (7.85 mmol) of azodicarboxylic acid diethyl ester dissolved in 2 ml of toluene are slowly added dropwise while stirring. The components are allowed to react for 2 hours at room temperature. For the work-up, the mixture is taken up in 300 ml of ethyl acetate, the organic phase is washed with water and brine ··· · · « · ·Β · · ··*** 4«’ 9** ··** and then dried over sodium sulfate. The crude product is chromatographed on silica gel /hexane/acetone, gradient, up to 4:1/. 1.40 g of 16a-formate is obtained, which is dissolved in 50 ml of 3% methanolic potassium hydroxide for saponification. After 1 hour of reaction at room temperature, aqueous hydrochloric acid is added to the mixture, taken up in 300 ml of ethyl acetate, the organic phase is washed with water and brine and dried over sodium sulfate. The crude product is chromatographed on silica gel /dichloromethane/ethyl acetate, gradient 7:3/· Yield 940 mg /63-s/.

8a-Estra-1,3,5/10/-triene-3,16a-diol (2)

740 mg /2.58 mmol/ methyl ether is dissolved in 25 ml of a 1.2 molar solution of diisobutylaluminum in toluene and the solution is refluxed at a bath temperature of 130°C with the exclusion of moisture /argon atmosphere/. The reaction mixture is then cooled in an ice bath and a mixture of ethyl acetate/water is carefully added. The precipitate is removed by filtration, washed thoroughly with ethyl acetate and the organic phase is concentrated in vacuo. The crude product is recrystallized from acetone/hexane. Yield 323 mg /46%/, mp 239-240°C, /a/ _D = +19.8° /c=0.52, methanol/.

Example 3

7a-Methyl-oestra-l, 3,5/10/-triene-3,16β-άϊο1

3-Methoxy-7a-methyl-oestra-1,3,5/10/-trien-17-one-17-phenylsulfonylhydrazone

From 4.70 g (15.75 mmol) of 3-methoxy-7a-methyl-estra-1,3,5/10/-17-one, 4.70 g (66%) of the corresponding phenylsulfonylhydrazone are obtained, which crystallizes out during cooling of the reaction mixture. M.p. 167-170°C.

3-Methoxy-7a-methyl-oestra-1,3,5/10/,16-tetraene

Olefination of 4.40 g (9.72 mmol) of phenylsulfonylhydrazone yields 2.35 g (85%) of olefin, which crystallizes from ethanol (hexane/ethyl acetate 9:1) as white flakes after chromatography on silica gel. M.p. 114-116°C.

17a-Bromo-3-methoxy-7a-methyl-oestra-1,3,5/10/-trien-16β-ol

From 2.00 g (7.08 mmol) of olefin, 2.14 g (80%% adduct) were obtained by bromohydrin formation; m.p. 145-146°C (ether/pentane), with decomposition.

3-Methoxy-7a-methyl-oestra-l, 3,5/10/-trien-16β-ol

Reductive dehalogenation of 1.94 g (5.12 mmol) of bromide yields 1.40 g (91%) of amorphous product.

7a-Methyl-oestra-1,3,5/10/-triene-3,16β-diol (3)

Cleavage of 1.40 g (4.66 mmol) of methyl ether yields 1.25 g (92%) of the diol; mp 209-210°C (acetone/hexane); /α/ _D = +73.8° (c=0.50, methanol).

Example 4

7a-Methyl-oestra-1,3,5/10/-triene-3,16a-diol (4)

From 0.74 g (2.58 mmol) of 3,Ιββ-diol, epimerization at C(16) and saponification gave 0.434 g (59%) of the 16a-derivative. Mp 217-219°C (acetone/hexane), /a/ _D = +84.4° (c= 0.52, methanol).

Example 5

1-Methoxy-oestra-l, 3,5/10/-triene-3,Ιββ-diol

1,3-Dimethoxy-estra-1,3,5/10/-trien-17-one-17-phenylsulfonylhydrazone

From 3.14 g (10 mmol) of 1,3-dimethoxy-oestra-1,3,5/10/-trien-17-one, 4.0 g (85%) of 17-benzenesulfonic acid hydrazone are obtained according to the general hydrazone formation procedure, which crystallizes from the ethanol reaction mixture. M.p. 200-202°C.

1,3-Dimethoxy-oestra-1,3,5/10/,16-tetraene

Olefination of 4.0 g (8.54 mmol) of hydrazone yields 1.96 g (76%) of tetraene, which is recrystallized after ethanol chromatography. M.p. 109-111°C.

1,3-Dimethoxy-estra-1,3,5/10/-trien-16β-ol

From 1.50 g (5.03 mmol) of olefin, 0.872 g (55%) of Ιββ-alcohol is obtained by bromohydrin formation and dehalogenation.

1,3-Dimethoxy-estra-1,3,5/10/-trien-16a-ol

Inversion of 0.50 g (1.58 mmol) of Ιββ-alcohol yielded 0.46 g (92%) of 16α-epimer.

1-Methoxy-oestra-1,3,5/10/-triene-3,Ιββ-diol (5)

From 0.25 g (0.79 mmol) of the 1,3-dimethoxy derivative, 0.18 g (75%) of mono-demethyl methoxydiol are obtained; after trituration with toluene, m.p. 90-93°.

Example 6

1-Methoxy-oestra-1,3,5/10/-triene-3,16a-diol (6)

0.35 g (1.11 mmol) of the dimethoxy derivative of the 16a series was demethylated to give 0.218 g (65%) of monomethyl ether. M.p. 240-242°C (acetone/chloroform)

Example 7

3,11β,16β-Trihydroxyoestra-1,3,5/10/-triene-11-nitrate ester

3,16β-diacetyloxy-oestra-1,3,5/10/-triene

8.00 g /29.4 mmol/ ostra-1,3,5/10/-triene-3,16β-diol are dissolved in 50 ml of pyridine at room temperature, 10 ml of acetic anhydride are added while stirring and left to react overnight. For the work-up, the reaction mixture is poured into 3 l of ice water, when the reaction product precipitates out. This is collected on a filter, washed thoroughly with dist. water, dried and taken up in 500 ml of dichloromethane. The organic phase is washed with dilute hydrogen carbonate solution and water and dried over sodium sulfate. The organic residue is recrystallized from an acetone/hexane mixture. Yield 8.40 g /80%.

3,16p-Diacetyloxy-9,1β-dihydroxy-oestra-1,3,5/10/-triene-1nitrate ester

7.85 g (22.0 mmol) of 3,16β-diacetyl-oestra-l, 3,5/10/-triene are suspended in 200 ml of aqueous (90%) acetic acid and 60.31 g (110 mmol) of cerammonium nitrate are added in portions over 10 minutes while stirring. The steroid adduct goes into solution during the reaction. After 5 hours, the reaction mixture is poured into 6 liters of ice water and the yellowish-red precipitate is filtered off with suction and then air-dried. The crude product is taken up in 600 ml of ethyl acetate, the organic phase is washed with water and brine and dried over sodium sulfate. The reddish-brown crude product is chromatographed on silica gel (dichloromethane/ethyl acetate 9:1), yield 5.10 g (53%), m.p. 173-175°C (acetone/hexane).

3,16β-Diacetyloxy-oestra-1,3,5/10/-triene-11β-ol-11-nitrate ester

To a solution of 2.42 g (5.58 mmol) of 3,16β-diacetyloxy-oestra-1,3,5/10/-triene-9,Ιΐβ-ol-11-nitrate ester and 2.90 ml (18.31 mmol) of triethylsilane in 60 ml of dry dichloromethane, cooled to -15°C, 5.0 ml of boron trifluoride etherate were added dropwise with stirring. The reaction was allowed to proceed for 1 hour at -15°C and then for a further hour at 0°C, and the reaction mixture was then poured into ice-water containing bicarbonate. The product mixture was extracted with dichloromethane, the organic phase was washed with water and dried over sodium sulfate. The crude product was chromatographed on silica gel (hexane/ethyl acetate 7:3). Yield 1.58 g (68%). M.p. 188-190°C (acetone-hexane).

3,11β,16β-Trihydroxyoestra-1,3,5/10/-triene-11-nitrate ester (7)

1.31 g (3.14 mmol) of the above diacetate is taken up in 60 ml of dichloromethane, 20 ml of 3% methanolic KOH solution is added and the mixture is stirred for 4 hours under a protective gas (argon) atmosphere. For the work-up, 500 μΐ of ethyl acetate is added, the mixture is diluted with dichloromethane, the organic phase is washed with water and dried over sodium sulfate. The crude product is recrystallized from dichloromethane. Yield 874 mg (83%); mp 170-171°C (decomposition); /a/ _D +68.9° (c 0.52, methanol).

Example 8

3,11β,16a-Trihydroxy-oestra-1,3,5/10/-triene-11-nitrate ester (8)

820 mg /2.46 mmol/ 3,16β-Oίο1ί are dissolved in 25 ml of dry tetrahydrofuran and 2.26 g /8.62 mmol/ triphenylphosphine and 325 μΐ formic acid are added. Finally, 1.34 ml /8.62 mmol/ azodicarboxylic acid diethyl ester is added to this solution at room temperature, while stirring, slowly dropwise. After complete addition, stirring is continued for 30 minutes at room temperature, then the reaction mixture is poured into water and extracted with ethyl acetate. The organic phase is washed with water and brine and dried over sodium sulfate. The crude product is taken up in 20 ml of dichloromethane, 10 ml of 3% methanolic KOH solution is added and the mixture is stirred at room temperature for 2.5 hours, excluding oxygen from the air. For work-up, dilute hydrochloric acid is added to the mixture, extracted with 200 ml of dichloromethane, washed with water and dried over sodium sulfate. The crude product is chromatographed on silica gel /dichloromethane/acetone, gradient up to 4:1/. Yield 704 mg /85%/ as a foam. /a/ _D +71.4° /c 0.50, methanol/.

Example 9

18a-Homoestra-l,3,5/10/-triene-3,16a-diol 3-Methoxy-18a-homoestra-l, 3,5/10/-triene-3,16a-diol

7.41 g of 3-methoxy-18a-homoestra-1,3,5/10/, 16-tetraene are dissolved in 50 ml of anhydrous tetrahydrofuran under a protective gas atmosphere and 6.4 g

...............

··· · · ····* · ··· borabicyclo/3,3,1/nonane can be reacted. The mixture is stirred at room temperature until complete dissolution. Finally, 75 ml of water is added. After the gas evolution has ceased, 45 ml of 3M NaOH solution is added. 45 ml of hydrogen peroxide /30%/ is added dropwise while cooling. The mixture is stirred at room temperature for 1 hour and then extracted with ethyl acetate. The crude product is chromatographed on silica gel /eluent: cyclohexane/ethyl acetate 3:1/; thus 6.03 g of 18a-homoestra-1, 3,5/10/-triene-3,16a-diol are obtained. Recrystallization from methanol gives colorless crystals; mp 109-lll°C, /a/ _D +71° /c 1.02, chloroform/.

18a-Homooestra-1,3,5/10/-triene-3,16a-diol (9) g of 3-methoxy-18a-homoestra-1,3,5/10/-trien-16a-ol is suspended in 40 ml of toluene under a protective gas atmosphere. 26 ml of a 30 vol.% solution of diisobutylaluminum hydride in toluene are added dropwise to this suspension and the mixture is refluxed until the conversion is complete /approx. 10 hours/. After cooling, 10.6 ml of ethanol and 32 ml of semi-concentrated hydrochloric acid are carefully added to the mixture while cooling. After extraction with ethyl acetate, 1.85 g of crude, title product is obtained. After recrystallization with ethyl acetate, 1.34 g of colorless crystals are obtained. Op 194-198°C; /a/ _D +69°/c 0.99, dioxane/.

Example 10

18a-Homoösztra-l,3,5/10/-triene-3,16β-άϊο1 (10)

0.5 g of 18a-homoestra-1,3,5/10/-triene-3,16a-diol is dissolved in 25 ml of toluene, with the addition of 3.66 g of triphenylphosphine and 3.42 g of 4-nitrobenzoic acid. 6.4 ml of azodicarboxylic acid diethyl ester (as a 40% solution in toluene) is slowly added dropwise. After a reaction time of 48 hours at room temperature, ethyl acetate is added and the organic phase is washed with sodium bicarbonate solution, water and sodium chloride solution. The solution is dried over magnesium sulfate and evaporated.

The product obtained is dissolved in 30 ml of methanol and 4.82 g of potassium carbonate are added. The solution is stirred at room temperature until complete saponification. For the work-up, the bulk of the methanol is distilled off and the residue is taken up in ethyl acetate. It is washed with sodium chloride solution and dried over magnesium sulfate. After evaporation, 0.45 g of the crude product of the title is obtained. After recrystallization from ethyl acetate, 0.26 g of colorless crystals are obtained; mp 210-213°C; /a/ _D +67°/c 1.01, dioxane/.

Example 11

18a-Homooestra-1,3,5/10/,9(11)-tetraene-3,16a-diol 18a-Homooestra-1,3,5/10/-triene-3,16a-diyl diacetate To 18a-homoestra-1,3,5/10/-triene-3,16a-diol, 4 ml of pyridine, 4 ml of acetic anhydride and 10 mg of dimethylaminopyridine were added and the mixture was left to stand overnight. For work-up, ice was added to the mixture and extracted with ethyl acetate. The combined extracts were washed with 10% copper sulfate solution and saturated sodium chloride solution and then dried over magnesium sulfate. 1.32 g of the title product was obtained as a colorless foam. /a/ _D +50°/c 1.08, chloroform/.

18a-Homooestra-1,3,5/10/,9/11/-tetraene-3,16a-diyl acetate To a mixture of 18 ml of methylene chloride, 18 ml of water, 15 ml of acetone, 5.4 g of sodium bicarbonate and 12 mg of tetra-n-butyl ammonium hydrogen sulfate, 1.32 g of 18a-homoestra-1,3,5/10/-triene-3,16a-diyl acetate are added. After warming to 10°C, 11.1 g of potassium monopersulfate (Caroat ^R ) are added in portions. The reaction mixture is stirred at 10°C for 4.5 hours. The salt is then filtered through a glass filter and the organic phase of the filtrate is separated. The aqueous phase is extracted with methylene chloride and the combined extracts are dried over magnesium sulfate. After distilling off the solvent, 1.73 g of crude 9a-hydroxy-18a-homoestra-1,3,5/10/-triene-3,16a-diyl diacetate is obtained. This is dissolved in 12 ml of methylene chloride. The solution is cooled to -10°C and 0.16 ml of 70% sulfuric acid is added. After the conversion is complete, saturated sodium bicarbonate solution is added and the organic phase is separated. After drying and distilling off the solvent, 1.33 g of a brown oil is obtained. After purification on silica gel (eluent cyclohexane:ethyl acetate 3:1) 0.63 g of the title product is obtained as a colorless foam. /a/ _D +123°/c 1.02, chloroform/.

18a-Homoestra-1,3,5/10/9/11/-tetraene-3,16a-diol (11)

0.63 g of 18a-homoestra-1,3,5/10/9/11/-tetraene-3,16a-diyl acetate is dissolved in 50 ml of methanol and 4.72 g of potassium acetate is added. The mixture is stirred at room temperature until complete saponification. For work-up, the bulk of the methanol is distilled off and the residue is taken up in ethyl acetate. The solution is washed with sodium chloride solution and dried over magnesium sulfate. Evaporation

After 0.49 g of 18a-homoestra-1,3,5/10/9/11/-tetraene-3,16a-diol is obtained in the form of yellowish crystals. M.p. 196-202°C; /a/ _D +163° (c 1, dioxane).

Example 12

Ostra-1,3,5/10/9/11/-tetraene-3,16a-diol

Ostra-1,3,5/10/9/11/-tetraene-3,16a-diyl acetate

By proceeding similarly to Example 11, 12.69 g (35.8 mol; 64% of theory) of oestra-1,3,5/10/9/11/-tetraene-3,16a-diyl acetate were obtained from 19.9 g (55.82 mmol) of oestra-1,3,5/10/9/11/-tetraene-3,16a-diyl acetate.

Ostra-1,3, 5/10/9/11/-tetraene-3,16a-diol (12)

Proceeding analogously to Example 11, 12.5 g (35.26 mmol) of oestra-1,3,5/10/9/11/-tetraene-3,16a-diyl acetate are saponified. 9.53 g (35.26 mmol); 99% of theory) of oestra-1,3,5/10/9/11/-tetraene-3,16a-diol are obtained in the form of almost colorless crystals. Recrystallization from ethyl acetate yields colorless crystals. Mp 237-244°C; /a/ _D +163 /c 1.12; dioxane/.

Example 13

13a-Estra-1,3,5/10/-triene-3,16a-diol

3-Methoxy-17-tosylhydrazono-13a-oestra-l, 3,5/10/-triene

2.5 g (8.79 mmol) of 3-methoxy-17-tosylhydrazono-13a-oestra-1,3,5/10/-trien-17-one and 1.96 g (10.55 mmol) of tosylhydrazide are refluxed in 15 ml of ethanol/ethyl acetate 4:1 (v/v) for 6 hours. The cooled reaction mixture is diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase is washed with saturated sodium bicarbonate solution and saturated sodium chloride solution and dried over magnesium sulfate. The resulting dark brown oil is chromatographed on silica gel (eluent cyclohexane/ethyl acetate 4:1). 2.49 g of a colorless, amorphous solid is obtained; /a/ _D -58° /c 0.99; dioxane/.

Methoxy 13a-oestra-l, 3, 5/10/,16-tetraene

2.43 g (5.37 mmol) of 3-methoxy-17-tosyl-hydrazono-13a-oestra1,3,5/10/-triene are suspended in 20 ml of anhydrous methyl tert-butyl ether. To this suspension is slowly added dropwise 1.61 ml of 10M n-butyllithium solution in hexane. The mixture is stirred for 1 hour at room temperature. 50% saturated ammonium chloride solution is added dropwise while cooling. The organic phase is separated and extracted with ethyl acetate. The combined organic phases are washed with water and saturated sodium chloride solution and dried over magnesium sulfate. The crude product (2.1 g of brownish oil) is chromatographed on silica gel. 0.81 g of 3-m-methoxy-13a-oestra-1,3,5/10/,16-tetraene is obtained as a colorless oil; (α/ _D -6°/c 0.94; chloroform).

3-Methoxy-13a-estra-1,3, 5/10/-trien-16a-ol

0.81 g (3 mmol) of 3-methoxy-13a-oestra-1,3,5/10/, 16-tetraene is dissolved in 10 ml of anhydrous tetrahydrofuran under protective gas and 0.73 g of 9-borabicyclo[3.3.1]nonane is added. The mixture is stirred at room temperature until the conversion is complete. Then 15 ml of water is added. After the gas evolution is complete, 7.8 ml of 3M NaOH is added, then 7.8 ml of (30%) hydrogen peroxide solution is slowly added dropwise while cooling. The mixture is stirred for 1 hour at room temperature and then extracted with ethyl acetate. Chromatography of the crude product on silica gel (eluent cyclohexane/ethyl acetate 4:1) yields 604 g of 3-methoxy-13a-estra-1,3,5/10/-trien-16a-ol in the form of a colorless oil.

13a-Estra-1,3,5/10/-triene-3,16a-diol (13)

0.55 g of 3-methoxy-13a-oestra-1,3,5/10/-trien-16a-ol is dissolved in 10 ml of hot toluene under protective gas. To this solution is added dropwise a mixture of 2.3 ml of diisobutylaluminum hydride and 5.4 ml of toluene and kept at this temperature until the conversion is complete /approx. 4 hours/. To the cooled mixture is added 2.1 ml of ethanol and, while cooling, 6 ml of semi-concentrated hydrochloric acid are carefully added. After extraction with ethyl acetate, the organic phase is washed until neutral and dried over magnesium sulfate. 362 mg of the title product is obtained. Recrystallization from methanol yields colorless crystals; mp 224-231°C; /a/ _{D +} 61° /c 1.13; pyridine/.

Example 14

9P-Estra-1,3,5/10/-triene-3,16a-diol

Prepared in a manner analogous to Example 13. Colorless foam.

3-Methoxy-9β-oestra-1,3,5/10/,16-tetraene

Prepared in a manner analogous to Example 13. Colorless oil.

3-Methylo-9β—oestra-1, 3,5/10/-trien-16a-ol

Prepared in a manner analogous to Example 13. Colorless oil.

9β-Estra-l, 3,5/10/-triene-3,16a-diol (14)

Prepared in a manner analogous to Example 13. Colorless crystals. M.p. 140-145°C; /a/ _D -91° /c 0.98, dioxane/.

Example 15

3_, 16a-Bis/benzyloxy/-18a-homoestra-1, 3,5/10/-trien-11-one

3,16a-Bis(benzyloxy)-18a-homoestra-1,3,5/10/,9/11/-tetraene g sodium hydride (25.52 mmol, 80% paraffin oil) was added to 32 ml anhydrous N,N-dimethylformamide under protective gas. To this mixture was added dropwise a solution of 7.67 g (26.97 mmol) of 18ahomoestra-1,3,5/10/-triene-3,16a-diol in 40 ml tetrahydrofuran. After the gas evolution had ceased, 13.84 g (80.91 mmol) of benzyl bromide was added. After the conversion was complete, the reaction mixture was slowly added dropwise to about 1 liter of water. After extraction with ethyl acetate, 14 g of a brown oil was obtained. Chromatography on silica gel gave 10.2 g (21.9 mmol, 81.3% of theory) of the title product as a colorless oil; /α/ο +110 /c 1.01, chloroform/.

3,16α Bis/benzyl oxy/-18a-homoestra-l,3,5/10/-trien-lla-ol g /21.5 ^ol/ 3,16a-bis/benzyl-oxy/-18a-homoestra-l,3,S/10/,-9/U/-tetraene is dissolved in 60 ml of anhydrous tetrahydrofuran under a protective gas atmosphere and 12.9 _{g /107} , _{61 Мо1/} catechol borane and 0.99 g /«,1 mmol/ lithium borohydride are added. After the conversion is complete, it is hydrolyzed by carefully adding 100 ml of water. Then 95 ml of 3N sodium hydroxide is added and 95 ml of 303 hydrogen peroxide is added dropwise while stirring. The mixture was stirred at room temperature for 1 hour and then extracted with ethyl acetate. The crude product was chromatographed on silica gel; eluent was cyclohexane/ethyl acetate 4:1. 8.73 g (18.08 of theory 84%) of the title product was obtained as a colorless foam. /a/„-48' /c 0.96, chloroform/

3'16a~Bis/benzyloxy/-18a-homoestra-1,3,5/10/-trien-11-one (15)

0.39 g (1.84 mmol) of 3,16a-Bis(benzyloxy)-18a-homoestral,3,5(10)-trien-111-ol was dissolved in 20 ml of methylene chloride and 0.98 g (4.6 mmol) of pyridinium chlorochromate was added. The mixture was stirred for 4 hours, then diluted with carbon tetrachloride and filtered through silica gel. The filtrate was evaporated and subjected to silica gel chromatography (eluent: cyclohexane/ethyl acetate 4:1). 0.63 g (1.31 mmol, 71% of theory) of the title product was obtained as colorless crystals. (a) _D +177° (c 0.96, chloroform). IR(v=C=O) 1705 cm' ¹ .

Example 16

3,16a-Bis/benzyloxy/-18a-homoestra-1,3, 5/10/-trien-11-one

3,16a-Bis/benzyloxy/-18a-homoestra-1,3,5/10/,9/11/-tetraene

Similarly to Example 15, from 8.7 g (32.17 mmol) of oestra1,3,5/10/,-9/11/-tetraene-3,16a-diol, 12.83 g (28.47 mmol, 88% of theory) of 3,16a-bis(benzyloxy)-oestra-1,3,5/10/,9/11/tetraene was obtained as a colorless oil. /a/ _D +96° /c 1, chloroform/

3,16a-Bis/benzyloxy/-estra-1,3,5/10/-trien-11a-ol. In analogy to Example 15, from 12.74 g (28.27 mmol) of 3,16a-bis/benzyloxy/-estra-1,3,5/10/,9/11/-tetraene, 9.43 g (20.2 mmol), 71% of theory, of 3,16a-bis/benzyloxy/-estra-1,3,5/10/,9/11/-trien-11a-ol was obtained.

5/10/-trien-11a-ol is obtained as a colorless oil. /α/ _D -44° / _c 1.02, chloroform/.

3,16a-Bis/benzyloxy/-estra-1,3,5/10/-trien-11-one (16)

Analogously to Example 15, from 3 g (6.4 mmol) of 3,16a-bis(benzyloxy)-estra-1,3,5/10/trien-11a-ol, 1.91 g (4.09 mmol), 64% of theory, of 3,16a-bis(benzyloxy)-estra-1,3,5/10/trien-11-one were obtained. /α/ _D +197° /c 0.96, chloroform/. IR(v=C=O) 1709 cm' ¹ .

Example 17

9g_-Methyl-18a-homoestra-l, 3,5/10/-triene-3,16a-diol

3,16α Bis/benzyl oxy/-9a-methyl-18a-homoestra-1,3,5/10/-triene

11-on ⁷⁰ :.. ·: E7 • · · · · · ·*· ♦· ··· «Rjr

Under protective gas, 0.8 g (7.13 mmol) of potassium tert-butylate is dissolved in 6.26 ml of tert-butanol. 0.8 g (1.66 mmol) of 3,16a-bis(benzyloxy)-18a-homoestra-1,3,5(10)-trien-17-one is dissolved in 15.57 ml of methyl iodide and added dropwise to the first solution. After 15 minutes, 50 ml of saturated sodium chloride solution is added. Extraction with ethyl acetate gives a yellow foam, which is chromatographed on silica gel (eluent: cyclohexane:ethyl acetate 7:1). 0.6 g (1.21 mmol, 73% of theory) of the title product is obtained as a colorless foam; /a/ _D +216° /c 1.03, chloroform/. IR(v=C=O) 1705 cm ^-1 .

3,16a-Bis/benzyloxy/-9a-methyl-18a-homoestra-1,3,5/10/-triene

0.76 g (1.54 mmol) of 3,16a-Bis(benzyloxy)-9a-methyl-18a-homoestra-1,3,5(10)-trien-11-one is weighed into a flask with 5 ml of triethylene glycol. A solution of 2.16 g (38.15 mmol) of potassium hydroxide in 15 ml of triethylene glycol and 1.54 g (30.8 mmol) of hydrazine hydrate are added to the mixture. This mixture is kept at 210°C for 4 hours. It is then diluted with saturated sodium chloride solution and extracted with ethyl acetate. The organic phases are washed with dilute hydrochloric acid, water and sodium chloride solution. The crude product is chromatographed on silica gel (eluent: cyclohexane/ethyl acetate 14:1). At this time, 0.66 g (1.37 mmol, 89% of theory) of 3,16a-bis(benzyloxy)-9a-methyl-18a-homoestra-1,3,5/10/triene precipitates in the form of a colorless oil.

/a/ _D +47° /c 0.93, chloroform/.

9a-Methyl-18a-homoestra-1,3,5/10/-trilene-3,16a-diol (17)

0.65 g (1.37 mmol) of 3,16a-bis(benzyloxy)-9a-methyl-18a-homoestra-1,3,5/10/-triene is dissolved in 20 ml of tetrahydrofuran, 0.65 g of palladium/carbon (10* Pd) is added and hydrogenated. The catalyst is filtered off and the filtrate is evaporated. 0.4 g (1.33 mmol, 97% of theory) of 9a-methyl-18a-homoestra-1,3,5/10/-triene3,16«-diol remains. Recrystallization from methanol gives colorless crystals, mp 210-215'C; /a/ _D +72' /c 0.99, dioxane/

Example 18

9a-Methyl-oestra-1,3,5/10/-triene-3,16g-diol

3, 16a-Bis(benzyloxy)-9a-methyl-oestra-1,3,5/10/-trien-11-one

Analogously to Example 17, from 0.497 g (1.06 mmol) of 3,16α-bis(benzyloxy)-oestra-1,3,5(10)-trien-11-one, 0.379 g _{( 0.78} mmol), the theoretical 73*-a(3,16α-bis(benzyloxy)-9a-methyloestra-3,5(10)-trien-11-one, was obtained as a colorless foam.

/α/ο+231° /c 1.03, chloroform/. IR(v=C=O)» 1709 cm' ¹ .

3,16a-Bis/benzyloxy/-9a-methyl-oestra-1,3,5/10/-triene

Analogously to Example 17, from 0.715 g (1.48 mmol) of 3,16α-bis(benzyloxy)-9a-methyl-oestra-1,3,5/10/-trien-1-one, 0.458 g (0.98 mmol), 66% of theory, of 3,16α-bis(benzyloxy)-9amethyl-oestra-1,3,5/10/-triene was obtained as a colorless oil. /a/ _D =+61° /c 1.16, chloroform/.

♦·♦ · · · ···

...· ·«* '1. ~ · .9a-Methyl-oestra-1,3,5/10/-triene-3,16a-diol (18)

Analogously to Example 17, 0.476 g (1.01 mmol) of 3,16a-bis(benzyloxy)-9a-methyl-oestra-1,3,5(10)-triene gave 0.292 g (1 mmol, 99% of theory) of the title product. Recrystallization gave colorless crystals. Mp 182-186°C; /a/ _D =+77° /c 0.99, dioxane/.

Example 19 11β-Methyl-18α-homoestra-1,3,5/10/-triene-3,16α-diol

3,16a-Bis/benzyloxy/-lla-methyl-18a-homoestra-1,3,5/10/-trienlipol

0.6 g (1.25 mmol) of 3,16a-bis(benzyloxy)-18a-homoestra1,3,5/10/-trien-11-one was dissolved in 20 ml of anhydrous tetrahydrofuran under protective gas. This solution was cooled to -15°C and 4.17 ml of 3M methylmagnesium bromide solution were added. After the reaction was complete, saturated ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The crude product was chromatographed on silica gel (eluent: cyclohexane/ethyl acetate 6:1). 0.59 g (1.18 mmol, 95% of theory) of the title product was obtained as a colorless oil. (a) _D = -1° / _c 0.99, chloroform.

3,16a-bis(benzyloxy)-lip-methyl-18a-homoestra-l, 3,5/10/-triene

0.5 g (1 mmol) of 3,16a-bis(benzyloxy)-11a-methyl-18a-homoestra-1,3,5(10)-trien-11p-ol is dissolved in methylene chloride under protective gas and 1.75 g (2.4 ml; 15.3 mmol) of triethylsilane is added. The mixture is cooled to -10°C and 5.69 g (5 ml, 40 mmol) of boron trifluoride etherate is added. After the conversion is complete, the

999 · 4 4 · ·« 4 4 4 . .* Λ. — * saturated sodium bicarbonate solution is added to the mixture and extracted. The crude product is purified on silica gel /eluent cyclohexane/ethyl acetate 9:1/. 0.327 g /0.68 mmol, 68% of theory/ of the title product is obtained as a colorless oil. /a/ _D =+119° /c 0.99, chloroform/.

lip-Methyl-18a-homoestra-1,3,5/10/-triene-3,16a-diol (19)

0.45 g (0.93 mmol) of 3,16a-bis(benzyloxy)-lip-methyl-18ahomoestra-1,3,5(10)-triene is dissolved in 20 ml of tetrahydrofuran, 0.45 g of palladium/carbon (105 Pd) is added and hydrogenated. The catalyst is filtered off and the filtrate is evaporated. 0.264 g (0.87 mmol, 94% of theory) of the title product remains. Recrystallization from ethyl acetate gives colorless crystals. Mp 244-251°C; /a/ _D =+197° /c 1.07, dioxane/.

Example 20 11β-Methyl-18α-homoestra-1,3,5/10/-triene-3,16β-diol (20)

0.1 g (0.33 mmol) of 11β-methyl-18α-homoestra-1,3,5/10/-triene3,16α-diol is dissolved in toluene, 0.35 g (1.33 mmol) of triphenylphosphine and 0.22 g (1.33 mmol) of 4-nitrobenzoic acid are added. To this, 0.6 ml (1.33 mmol) of diethyl azodicarboxylic acid ester (40% toluene solution) is slowly added dropwise. The mixture is kept at 50°C until the conversion is complete. It is then diluted with ethyl acetate and the organic phase is washed with sodium bicarbonate solution, water and sodium chloride solution. It is dried over magnesium sulfate and evaporated.

»·'« , ··'*·♦»·· ··· · · « ·*, ··· ·*· * ·» * *♦ '

The product obtained is dissolved in 20 ml of methanol and 0.81 g (5.85 mmol) of potassium carbonate is added. The mixture is stirred at room temperature until complete saponification. For the work-up, the bulk of the methanol is distilled off and the residue is taken up in ethyl acetate. The solution is washed with sodium chloride and then dried over magnesium sulfate. The crude product is chromatographed on silica gel (eluent cyclohexane/ethyl acetate 2:1). 0.79 g (0.26 mmol, 78% of theory) of the title product is obtained. Colorless crystals are obtained by crystallization from ethyl acetate. mp 175—188 C; /a/ _D =+110° /c 0.95, dioxane/.

Example 21

ΙΙβ-Methyl-oestra-l, 3,5/10/-triene-3,16a-diol

3,16a-Bis/benzyloxy/-11a-methyl-18a-homoestra-1, 3, 5/10/-trien11β—ol

The procedure is as in Example 19. Colorless oil; /a/ _D =+2 ° /c 0.92, chloroform/.

3, 16α Blsz/benzyloxy/-11β-methyl-estra-1,3,5/10/-triene

We proceed as in Example 19. Colorless oil; /a/ _D =+112° /c 1, chloroform/.

11β-Methyl-18a-homoestra-1,3,5/10/-triene-3,16a-diol (21)

The procedure is as in Example 19. Colorless crystals from methyl tert.butyl ether. M.p. 243-250°C; /a/ _D =+172° /c 0.96, dioxane/.

Example 22 11g-Methyl-oestra-1,3,5/10/-triene-3,16β-dlol (22)

Prepared similarly to Example 20. Colorless crystals from cyclohexane/ethyl acetate. m.p. 194-199°C. /«/„.+177° /o 0.97, dioxane/.

Example 23 Lip-ethyl-15a-homoestra-1,3,5/10/-triene-3,16g-diol

Prepared according to Example 19. Colorless oil.

3,16a-Bis/benzyloxy/-liR-ot-i η ο-, ..

' np ethyl l°a-homoestra-l, 3,5/10/-triene

Prepared according to Example 19. Colorless oil.

UP-Ethyl-18a-homoestra-1,3,5/10/-trilene-3,16a-diol(23)

Proceeding analogously to Example 19. Colorless crystals, m.p. 242-255°C; /α/„=+130° /c 0.99, pyridine/.

Example 24 11g-Ethyl-18a- _homoestra -1,3,5/10/-triene-3,16g-diol (24)

The procedure is analogous to Example 20. Colorless crystals, mp 152-156°C; /a/ _D =+148° /c 0.95, dioxane/.

Example 25 11g-Ethyl-ester _a -1,3,5/l0/-triene-3,16a-diol ³ U6«-Bis/benzyl- _O xi/-i _la .ethyl _-ester _ ₁ , _3r5 ^^

We proceed analogously to Example 19. Colorless oil, /a/ _D =-3 /c 1, chloroform/.

3,16a-Bis(benzyloxy)-lip-ethyl-oestra-1,3,5/10/-triene

The procedure is analogous to Example 19. Colorless oil, /a/ _D =+97° /c 1, chloroform/.

ΙΙβ-Ethyl-oestra-1,3,5/10/-triene-3,16a-diol

Proceeding analogously to Example 19. Colorless crystals from ethyl acetate. M.p. 245-250 °C;/a/ _D =+104° (c 1, dioxane).

Example 6

IIβ-Ethyl-oestra-1,3,5/10/-triene-3,16β-άίο1 (26)

We proceed analogously to Example 20. Amorphous solid.

example

ΙΙβ-Methoxy-estra-1,3,5/10/-triene-3,16a-diol 11β-Methoxy-17-tosyl-hydrazono-estra-1,3,5/10/-trien-3-ol To a mixture of 1 g (3.3 mmol) of 3-hydroxy-11β-methoxy-estra-1,3,5/10/-trien-one and 0.7 g (3.8 mmol) of toluene-4-sulfonic acid hydrazide are added and the mixture is heated to reflux. After a reaction time of about 5 hours at this temperature, the reaction mixture is cooled and the product is isolated by dropping it into about 100 ml of water. The crude product is boiled in n-hexane and the water formed is thus removed azeotropically. 1.14 g (73% of theory) of product is obtained.

ΙΙβ-Methoxy-oestra-l, 3 5/in/ ic 4-^+.

^x ' j, □/iu/, 16-tetraen-3-ol ⁴ °° mg /1 mmol/ HP-methoxy-17-tosyl-hydrazono-estral,3,5/10/-trien-3-ol is weighed in under 15 gas and intensive stirring

Add 1 ml (10 mmol) of 10M n-butyl-llti™ solution in n-hexane at room temperature and heat to reflux. About 10 minutes.

After the reaction mixture was worked up, ammonium chloride solution and 30 ml of saturated ethyl acetate were added dropwise. The organic phase was washed with water/brine and dried over sodium sulfate. The crude product was added to silica gel (60% of theory).

11-acetate 1:1/. Extraction

170

IIP Methoxy 3-methyl- _s2 -ylyloxy-oestra-l, 3,5/10/, 16-tetraene

234 mg /1 ™ol/ Ιΐβ-methoxy-oestra-1, 3,5/10/-tetraen-3-ol .butyl methyl ether and 1 _m i _p i _{ricline e} i _otherwise θ θ triethyl bromosilane can be reacted. After 1 _hour , 30 ml of vi ml is added to the reaction mixture.

dried and evaporated in vacuo.

The organic phase is separated, washed,

The oily product thus obtained was immediately transferred to the next step (hydroboration). Yield 380 mg (95% of theory).

11β Methoxy—oestra-1 3 ^/m/ +.

' , /10/ triene-3,16a-diol (27)

330 mg /0.95 mmol/ HP-methoxy^-triethyl-sini-oxy-estra1.3,5/10/,16-tetraene are dissolved in 20 ml of tetrahydrofuran under an inert gas atmosphere. 464 mer /o _ö . , mg /3.8 mmol/ 9-borabicyclo/3.3.1/nonane are added after the reaction mixture has completely dissolved at room temperature. Then 5 _ml of water are added dropwise after the gas evolution has ended, 2 ml of 5N NaOH hydrogen peroxide solution is added, this solution is then added dropwise and 2 ml of 30%-o at room temperature. The stirring is continued for 1 hour with ethyl acetate and the product obtained is chromatographed by /n-hexane/kl, then

The crude product obtained was crystallized from a silica gel oroform/methanol 45/45610/purified colorless ethyl acetate/n-hexane mixture. 230 mg of theoretical 80% /a/ _D =+101° /c 0.53, dioxane/.

M.p. 212-222°C;

Example 28

11β Methoxy-estrA-1 3 s/m/ + · ' --------------g_4z-^z5/10/-tr _1en _3 _fl6 p_ _{diol (28)}

225 (0.76 mmol) np-methoxy-srtra-j, 3, 5/10/-trié„-3,16α ^tO1U ° ^lban ° ^ldUnk triphenyl- _phosphine (6.8 mmol) 4-nitro-benzoic acid. To this is added dropwise 2.7 ml (6 qi / ' ml /6.8 mmol) 40% toluene azo drcarboxylic acid diethyl ester solution hu - xate. After a reaction time at room temperature, ethyl acetate is added to the reaction mixture and the resulting organic phase is washed with sodium bicarbonate solution.

nuts 30 and

1.4 g solution per hour

The resulting sodium chloride solution is opened with water, and then the product is taken up in methanol.

after adding the

A suspension of 2.5 g of potassium saponification is refluxed. For the work-up, the catalyst and the crude product are washed with ethyl acetate, water and sodium chloride solution and dried. The solution is taken up in acetate from a chloroform/cyclohexane mixture, and after evaporation and crystallization, colorless crystals are obtained - iας , 195 mg /theoretical 85 ^& -α/ μ

195-200°c,· /α/ ^2ο _η -+ _1Ο ι ° , , ^aPUnk · °· ^ρ · ^{77 D-+101 /c} Flavor 18, dioxane/.

Example ²⁹

HP Phenyl ester 1.3 s/m/ +. · --------^zVigZztrien- 3.16g-di ο Ί ^dlk · The solid is filtered. 450 mg

UP- _Phenyl -l ₇ . _to2il . _hydrazone

1,J,b/10/-trien-3-ol

SM mg /1.71 mmol/ was reacted with toluene-4-sulfo ^Ρ θ thioic acid hydrazide in a _clindulation manner. After cooling _{the reaction} mixture, in this case, the _product which _precipitated in part was filtered off with suction, washed with ethanol and gave yellowish crystals (theoretical 512--^/ ' a/).

In the mother liquor still

38%—a.

The remaining product can _be isolated by extraction reaction and appropriate ^work _{- up} . 303 _mg ,

11β phenyl-oestra-1,3 5/in/ ir ' J, 5/10/, 16-tetraen-3-ol

515 mg /1 mmol/ 11R_x _enyl , /10/1· , iPlohil-1'-tozri-hydrazono-estra-1,, 5/10/-trien-3-ol _t a ₂₈ . _{Example S2erlnt}

1Í+-· -L ml /10 mmol/ n-but-ii: _k ^{Solution gives the product r} — - - -rs, which is converted into triethylsilyl ether in the next step.

ameA 28.

silyl-oestra-1,3,5/10/,16-tetraene

As an example, 450 mg of tetraen-3-ol is converted into ^triethyl _{silyl ether} with two silica gels. The product obtained is purified and the solution is evaporated in vacuo.

-acetate

An oily substance is obtained. Yield 320 mg _{/a2 (72% of theory) of 3,17} -tozr-hydrazono-estra-1,3,5/10/-trien-3-ol.

515 mg 11β-phenyl coated/.

¹¹ P- ^Fe n- _ÖS2 tza-l, ₃ ,5/ ₁ o/-triene-3,16a- _d i ₀₁ (29)

By hydroboration according to Example 27, 320 ™ ^ο1/ UP-phenyl-3-triethyl processing, silica!

mg /0.72 silyl-oestra-1,3,5/10/, 16-tetraene, after purification by chromatography /uuxuoi/ethyl acetate 70/7n/ ' t '0/30/ methanol 183 mg of the title compound.

m yields products according to. 0 p /«/ ² %=-103° /c 0.09, dioxane/.

crystallization

254-261°C;

Example 30 ^-^i^tr^l^^^ 16B d· i nn

-------—-3/ibp-diol (30)

The inversion of the 16-hydroxy group was carried out in Example 28. 36 mg /0.1 mmol/ HB- _phenyl · .

, „ ^1P feml-ostra-1,3,5/10/-triene3,16a-diol from silica.6i 1______ according to drive from toluene crystallization

After crystallization, 25 g of colorless crystals are obtained, m.p.

31, dioxane/.

2-L/ethyl acetate 70/30/ mg /of theory 69%241 247 °C; /a/ ²⁰ _D =-93

Example 31

3-hydroxy-le-homoestra-1,3,5/10/-trien-16-one

2.4 g per ton 2.5

18a homo-oestra-1 3 s/m/ +. · l,3,5/10/-trien-3,16a-diol 60 m!

ml of methylene chloride, this solution is cooled to 10c and dissolved in chromic sulfuric acid /8 mol/1 _chromate . This is added dropwise

4.2 ml anion/. After the conversion is complete, sodium bisulfite solution is added and its mass is distilled. To the remaining material, approx. is added. Finally, the precipitated steroid is filtered off with suction.

acetone boils 100 ml of water

2.02 g of the title product are obtained.

After drying in. O.p.

² 64-266°C; /a/ _D =- ₁₁₅ ' _{/c 0} .743, pi _ridin/ .

colorless crystals form16α ethynyl 18a—homo—oestra-1 35/10/¼ i,3,5/10/-triene-3,16p-diol (31)

At a temperature of about 0°C, 20 ml of tetrahydrofuran are added. Then, cooling and stirring with ethyne, a solution of n-butyllithium is added to the mixture. The temperature rises to about 0°C, and 3.4 ml (8.4 mmol) of 2.5M is added to the mixture.

The other

1,3,5/10/-trien-16-one lithium acetylide suspension/0.5 mmol/3-hydroxy-18a-homoestratate. After a reaction time of 30 minutes, approx.

hydrochloric acid is added.

The solution prepared with tetrahydrofuran was distilled at 0°C and the residue was added to the reaction mixture in toluene, then the organic phase was washed with water, the phases were separated, and the crude product was purified from the solution vacuum product (7:1) and toluene. 131 mg / _{of the} theoretical rr° / , ^letl 85,-a/ crystalline ethers

Punk. mp 197-202° _C ; _/a/2 » _D=+100 . _{/c 1/06; diox} . _nA ka32. example ——ethynyl_18a homo-ester^-i 3 ' ------1—í—/10/ trien-3,16a-diol (32)

The production of the product is carried out on the 31st.

we're done.

The reaction temperature is analogous to that described in the example. The higher the 16P-ethynyl ratio, the higher the yield at room temperature. It can be determined by chromatography on silica gel. Yield (cyclohexane/ethyl acetate 3:1) of the product is ²⁰ _D -+48° /c 1.04, 20% of theory; mp 213-219°C;

dioxane/.

Example 33

11β fluorine 7g methyl-oestra-1,3,5/10/-triene-3,16B-diol1 ¹¹ ^'-^-^-ethyl-astra-1 , 3, 5/10/-triene-3, 16a-diol

11β Fluorine 7α methylestr-4-ene-3,17-dione

15.2 g (79.8 mmol) of copper iodide are suspended in 70 ml of furan and the suspension is cooled to 0°C, cooled to 28.7 g (330 mmol) of lithium bromide and 27.8 ml of DMPU are added, stirred at this temperature for 30 minutes and

While mixing

Cool to -30°C.

52 bromide in a 3M diethyl ether solution is added dropwise, additional ml of methyl magnesium is stirred for 30 minutes, then 10.0 g (34.7 mmol) of HP-fluoro-oestra-4,6-diene-3,17-dione, 24.3 ml of

-1 trimethylsilyl chloride in _{60 ml} dichloromethane.

DMPU and after 23 is completed, mix for another 1.5 hours

The addition is at room temperature, then the cooling bath is removed, and 35 ml is added carefully, while stirring vigorously.

C to -10°C. For the work-up, the reaction mixture is washed with ethyl acetate and ethyl acetate saturated aqueous ammonium chloride solution until copper-free and the organic phase is purified by silica gel gradient 1:1. The extraction is dried over sodium sulfate. The chromatograph is performed (hexane/ethyl acetate, 3.1 g /30%/).

J. Τ* Τ’* lip-Fluoro-3-hydroxy-7a-methyl-oestra-1,3,5/10/-trien-17-one

To 8.3 g (27.2 mmol) of Ιΐβ-fluoro-7α-methyl-estr-4-ene-3,17-dione in 260 ml of acetonitrile was added 7.0 g (31.3 mmol) of copper(II) bromide and the reaction mixture was stirred for 7 hours at room temperature. For the work-up, ethyl acetate was added to the reaction mixture, the organic phase was washed with aqueous ammonium chloride solution, sodium bicarbonate solution, then with water and dried over sodium sulfate. The crude product was chromatographed on silica gel /toluene/ethyl acetate, gradient up to 7:3/. Yield 3.3 g (40%). /a/ _D =+166.8° /c 0.5, methanol/.

3-Acetyloxy-1,3-fluoro-7a-methyl-oestra-1,3,5/10/-trien-17-one

3.0 g (9.9 mmol) of Ιΐβ-fluoro-3-hydroxy-7α-methyl-oestra-1,3,5/10/-trien-17-one are dissolved in a mixture of 12 ml of pyridine and 6 ml of acetic anhydride and the reaction is allowed to proceed overnight at room temperature. For the work-up, the reaction mixture is mixed with ice water, then the precipitate is filtered off with suction and taken up in ethyl acetate. The organic phase is first washed with dilute hydrochloric acid and then with water and dried over sodium sulfate. 3.4 g of product is obtained, which is sufficiently pure for further work-up.

3-Acetyloxy-11β-fluoro-7α-methyl-oestra-1, 3,5/10/, 16-tetraene .7 g /7.9 mmol/ 3-acetyloxy-11β-fluoro-7α-methyl-oestra1,3,5/10/-trien-17-one prepared in 40 ml of dried dichloromethane is added 3.8 g /18.4 mmol/ 2,6-di-tert.butyl-4-methyl-pyridine, cooled to 0°C in a protective gas /argon/ atmosphere and 2.64 ml /16 mmol/ are added dropwise while stirring

...· ·..* 4. —·...· trifluoromethanesulfonic acid hydride. The cooling bath is removed and stirring is continued for 1.5 hours at room temperature. For work-up, ethyl acetate is added to the mixture, the organic phase is washed with water and dried over sodium sulfate. The crude product (6.0 g / 15 ml) is taken up in dimethylformamide, 5.72 ml of tributylamine, 0.11 g / 0.15 mmol/ bis/acetato/-bis/triphenylphosphine/-palladium and 0.61 ml / 16 mmol/ formic acid are added at room temperature and the mixture is stirred for 30 minutes at a bath temperature of 60°C /under an argon atmosphere/. For the work-up, the mixture is poured into ice water, extracted with ethyl acetate, the organic phase is washed first with dilute hydrochloric acid, then with water and dried over sodium sulfate. The crude product is chromatographed on silica gel /heptane/acetone, gradient up to 9:1/. Yield 1.71 g /66%/.

HP-fluoro-7a-methyl-oestra-1,3,5/10/-triene-3,16p-diol (33a)

1.67 g (5.22 mmol) of 3-acetyloxy-lip-fluoro-7a-methyl-estra1,3,5/10/, 16-tetraene are dissolved in a mixture of 30 ml of DMSO and 2.4 ml of water and 1.36 g of N-bromosuccinimide are added in portions at 0°C while stirring. After the total amount has been added, the cooling bath is removed and stirring is continued for 45 minutes at room temperature. For work-up, the reaction mixture is poured into ice water, extracted with ethyl acetate, the organic phase is washed with water and dried over sodium sulfate. The crude bromohydrin (2.3 g) is taken up in 25 ml of dry tetrahydrofuran, 5 ml (18.6 mmol) of tributyltin hydride is added, then first a spatula tip of AIBN (200 mg distributed over the entire reaction time) and stirring is continued for 10 hours at a bath temperature of 80°C under an argon atmosphere. For work-up, the mixture is diluted with ethyl acetate, the organic phase is washed with dilute hydrochloric acid and water and dried over sodium sulfate. For saponification, the crude product is dissolved in a mixture of 50 ml of methanol and 5 ml of dichloromethane and 2.0 g of potassium carbonate is added. The reaction mixture is stirred for 1.5 hours under argon and poured into ice water for work-up. The organic phase is washed with water and dried over sodium sulfate. The crude product is chromatographed on silica gel (chloroform/tert-butyl methyl ether, gradient up to 95:5). Yield 1.16 g (75%). Mp 239-240°C with decomposition; /a/ _D =+96.8° /c 0.51, methanol/.

Ιΐβ-fluoro-7a-methyl-oestra-1,3,5/10/-triene-3,16a-diol (33b)

0.60 g (2.0 mmol) of Ιΐβ-fluoro-7α-methyl-ostra-1, 3, 5/10/-triene3,16β-όϊο1ί is dissolved in 20 ml of dry tetrahydrofuran and 1.82 g (6.9 mmol) of triphenylphosphine and 0.26 ml of formic acid are added. 1.10 ml of DEAD is added dropwise to this solution under argon atmosphere, while cooling, at room temperature. After a reaction time of 30 minutes, it is diluted with water, extracted with ethyl acetate, the organic phase is washed with water and dried over sodium sulfate. The crude product is purified by silica gel chromatography (dichloromethane/ethyl acetate, gradient up to 95:5). The resulting formates are dissolved in 15 ml of dichloromethane, 7.5 ml of 3% methanolic potassium hydroxide are added and the mixture is left to stand for 2 hours under an argon atmosphere. For work-up, aqueous acetic acid is added, extracted with ethyl acetate, the organic phase is washed with water and dried over sodium sulfate. The crude product is purified by crystallization from acetone/hexane. Yield 0.45 g /75%/, m.p. 221-222 C with decomposition; /α/ο=+104.2° /c 0.52, methanol/.

The following compounds were prepared in an analogous manner to that described in Examples 3 and 4: 7a-phenyl-oestra-1,3,5/10/-triene-3,1ββ-diol, m.p. 239-241°C /acetone/hexane/ 7β-ίβηϋ-03ζίη3-1,3,5/10/-triene-3,1ββ-diol, m.p. 171-173°C /acetone/hexane/ 7a-ethyl-oestra-1,3,5/10/-triene-3,1ββ-diol, amorphous 7a-ethyl-oestra-1,3,5/10/-triene-3,16a-diol, m.p. 192-193°C /acetone/hexane/ 7a-ethyl-oestra-1,3,5/10/-triene-3,Ιββ-diol, amorphous 7β-ethyl-oestra-1,3,5/10/-triene-3,16a-diol, m.p. 187-189°C /acetone/hexane/ 7β-ethyl-oestra-1,3,5/10/-triene-3,Ιββ-diol, m.p. 156-157°C /dichloromethane/hexane/.

Table 1

Oestrogen here is RBA* hER β RBA* ΕΚβ/ERa rat uterus ER(RBA) rat prostate ER(RBA) prostate ER/uterus ER estradiol 100 100 1 100 100 1 estrone 60 37 0.6 3 2 0.8 17α- estradiol 58 11 0.2 2.4 1.3 0.5 estriol 14 21 1.5 4 20 5 5-Andostene- diol 6 17 3 0.1 5 50 genistein 5 36 7 0.1 10 100 cowboy 94 185 2 1.3 24 18

Table 2

Compound or example rat ER (RBA) uterus rat ER(RBA) prostate 50% bone protection /gg/Tier/ 50% uterine stimulation /pg/Tier/ 16a-Ostradioic 9 50 3 30 9 5.3 59 10______________ 1 13 7β-β1ί1-03ζ1Γβ-1,3,5(10)-triene-3,Ιββ-diol 0.2 2 7a-ethyl-oestra-1,3,5(10)-triene-3,16-diol 11 143 7β-phenyl-oestra-1,3,5(10)-triene-3,Ιββ-diol 0.7 14 7a-phenyl-oestra-1,3,5(10)-triene-3,Ιββ-diol 2.9 9 7β-ίθηϊ1-03ζ1Γ3-1,3,5(10)-triene-3,16a-diol 0.2 1.3 7β-ethyl-oestra-1,3,5- (10) -triene-3,16a-diol 0.1 2.9 4 29 200 3 5, 6 83

7α-thiomethyl-estra-l,3,5(10)-triene-3, Ιββ-diol, 7α-cyanomethyl-estra-1,3, 5(10)-triene-3, Ιββ-diol, 7β-ethyl-estra-l, 3,5 (10)-triene-3, Ιββ-diol, 7β-propyl estra-l,3,5(10)-triene-3,Ιββ-diol, 7β-ί-ρηορΐ1-05ζ1Γ3-1,3,5(10)-triene-3, Ιββ-diol, 7β-ί-ρ _Γ ορθηΐ1-03ζ1η3-1,3,5(10)-triene-3, Ιββ-diol, * · Μ ♦ « · .4.· ·..· 4.

7β-phenyl-oestra-1,3,5(10)-triene-3,Ιββ-diol, 7β-methoxy-oestra-1,3,5(10)-triene-3,1ββ-diol, 7β-thiomethyl-oestra-1,3,5(10)-triene-3,Ιββ-diol,

7β-cyanomethyl-oestra-1,3,5(10)-triene-3,Ιββ-diol,

15a-methyl-oestra-1,3,5(10)-triene-3,16a-diol,

15a-ethyl-oestra-1,3,5(10)-triene-3,16a-diol,

15a-propyl-oestra-l,3,5(10)-triene-3,16a-diol, 15a-allyl-oestra-l,3,5(10)-triene-3,16a-diol, 15a-i-propyl-oestra-l,3,5(10)-triene-3,16a-diol, 15a-i-propenyl-oestra-l,3,5(10)-triene-3,16a-diol, 15a-methoxy-oestra-l,3,5(10)-triene-3,16a-diol, 15a-thiomethyl-oestra-l,3,5(10)-triene-3,16a-diol, 15a-methyl-oestra-l,3,5(10)-triene-3,Ιββ-diol, 15a-ethyl-oestra-l,3,5(10)-triene-3,Ιββ-diol, 15a-propyl-oestra-l,3,5(10)-triene-3,Ιββ-diol, 15a-allyl-oestra-l,3,5(10)-triene-3,Ιββ-diol, 15a-i-propyl-oestra-l,3,5(10)-triene-3,Ιββ-diol, 15a-i-propenyl-oestra-l,3,5(10)-triene-3,Ιββ-diol, 15a-methoxy-oestra-l,3,5(10)-triene-3,Ιββ-diol, 15a-thiomethyl-oestra-l,3,5(10)-triene-3,Ιββ-diol, ^-methyl-oestra-l, 3, 5(10)-triene-3,16a-diol,

15β-θίί1-03Ζίη3-1,3,5(10)-triene-3,16a-diol,

15β-propyl-oestra-l,3,5(10)-triene-3,16a-diol, 15β-allyl-oestra-l,3,5(10)-triene-3,16a-diol, ·♦* ♦ · · ··· ···

15β-i-propyl-oestra-1,3,5(10)-triene-3,Ιβα-diol,

15β-i-propenyl-oestra-1,3,5(10)-triene-3,16a-diol,

15β-niethoxy-oestra-1, 3,5(10)-triene-3,16a-diol,

15β-thiomethyl-oestra-1,3,5(10)-triene-3,16a-diol,

15β-methyl-oestra-1,3,5(10)-triene-3,Ιββ-diol,

15β-θίί1-03ζίη3-1,3,5(10)-triene-3,Ιββ-diol,

15β-ρηορί1-03Ζ1η3-1,3,5(10)-triene-3,Ιββ-diol,

15β-311ϊ1-03ζίη3-1,3,5(10)-triene-3,Ιββ-diol,

15β-i-propyl-oestra-1,3,5(10)-triene-3,Ιββ-diol,

15β-i-propenyl-oestra-1,3,5(10)-triene-3,Ιββ-diol,

15β-methoxy-oestra-1,3,5(10)-triene-3,Ιββ-diol,

15β-thioInethyl-oestra-l,3,5(10)-trien-3, Ιββ-diol,

7a-trifluoromethyl-1^-fluoro-oestra-1,3,5(10)-triene-3,16α-diol,

7a-pentafluoroethyl-1^-fluoro-oestra-1,3,5(10)-triene-3,16α-diol,

7α-βϋ1-11β-ίfluoro-estradiol-1, 3,5 (10) -triene-3,16a-diol,

7a-propyl-1,3,5(10)-fluoro-oestra-1,3,5(10)-triene-3,16a-diol,

7α-ί-ρΓορϋ-11β-ί: luoro-estra-1,3,5(10)-triene-3,16a-diol,

7a-1-propenyl-1,3,5(10)-fluoro-oestra-1,3,5(10)-triene-3,16a-diol,

7a-phenyl-11β-fluoro-oestra-1,3,5(10)-triene-3,16a-diol, 7a-methoxy-11β-fluoro-oestra-1,3,5(10)-triene-3,16a-diol, /a-thiomethyl-11β-fluoro-oestra-1,3,5(10)-triene-3,16a-diol, 7a-cyanomethyl-11β-fluoro-oestra-1,3,5(10)-triene-3,16a-diol, 7p-ethyl-11β-fluoro-oestra-1,3,5(10)-triene-3,16a-diol, 7p-propyl- _11β -ostra-1,3,5(10)-triene-3,16a-diol, 7β-i-propyl-lip-fluoro-estra-1,3,5(10)-triene-3,16a-diol, 7β-i-propenyl-1β-fi _U or-estra-1,3,5(10)-triene-3,16a-diol, 7β-phenyl-lip-fluoro-estra-1,3,5(10)-triene-3,16a-diol, 7β-methoxy-lip-fluoro-estra-1,3,5(10)-triene-3,16a-diol, ^{7β -} thiomethyl-lip-fluoro-estra-1,3,5(10)-triene-3,16a-diol, 7β-cyanomethyl-lip-fluoro-estra-1,3,5(10)-triene-3,16a-diol, 7a-ethyl-lip-fluoro-estra-l,3,5(10)-triene-3,16p-diol, 7a-propyl-lip-fluoro-estra-l,3,5(10)-triene-3,16p-diol, 7a-i-propyl-llp-fluoro-estra-l,3,5(10)-triene-3, 16p-diol, 7a-i-propenyl-llp-fluoro-estra-l,3,5(10)-triene-3, 16p-diol, 7a-phenyl- _llp -fluoro-estra-l,3,5(10)-triene-3,16p-diol, 7a-methoxy-lip-fluoro-estra-l,3,5(10)-triene-3,16p-diol, 7a-thiomethyl-11β-fluoro-oestra-1,3,5(10)-triene-3,16β-diol, 7a-cyanomethyl-11β-fluoro-oestra-1,3,5(10)-triene-3,16β-diol, 7β-ethyl-11β-fluoro-oestra-1,3,5(10)-triene-3,16β-diol,

7p-propyl-llp-fluoro-oestra-1,3,5(10)-triene-3, Ιββ-diol, 7β-i-propyl-llβ-fluoro-oestra-1,3,5(10)-triene-3, Ιββ-diol, 7β-i-propenyl-llβ-fluoro-oestra-1,3,5(10)-triene-3, Ιββ-diol, 7β-ίβηί1-11β-ίfluoro-oestra-1,3,5(10)-triene-3, Ιββ-diol, 7β-Inethoxy-llβ-fluoro-oestra-1, 3,5 (10) -triene-3, Ιββ-diol, 7β-thiomethyl-llβ-fluoro-oestra-1, 3,5(10)-triene-3, Ιββ-diol, 7β-cyanomethyl-11β-fluoro-oestra-1,3,5(10)-triene-3,16α-diol, 15α-methyl-11β-fluoro-oestra-1,3,5(10)-triene-3,16α-diol, 15α-θΗ1-11β-ί fluoro-oestra-1, 3, 5 (10) -triene-3,16α-diol, 15α-propyl-11β-fluoro-oestra-1,3,5(10)-triene-3,16α-diol, 15α-311ί1-11β-ί fluoro-oestra-1,3,5(10)-triene-3,16α-diol, 15α-i-propyl-1^-fluoro-oestra-1, 3,5 (10)-triene-3, 16α-diol, 15α-i-propenyl-llβ-fluoro-estra-l,3,5(10)-triene-3,16a-diol, 15α-Iethoxy-llβ-fluoro-estra-l, 3,5 (10) -triene-3,16a-diol, 15α-thiopimeethyl-llβ-fluoro-estra-l, 3,5 (10) -triene-3,16a-diol, 15α-methyl-llβ-fluoro-estra-l,3, 5(10)-triene-3, Ιββ-diol, 15α-ethylϋ-ΙΙβ-fluoro-estra-l,3,5(10)-triene-3, Ιββ-diol, 15α-propyl-llβ-fluoro-estra-l,3,5(10)-triene-3, Ιββ-diol, 15α-η11ϋ-11β-ίfluoro-estra-1,3,5 (10) -triene-3, Ιββ-diol, 15α-i-propyl-11β-fluoro-estra-1,3,5 (10) -triene-3, Ιββ-diol,

15a-i-propenyl-lip-fluoro-oestra-1, 3,5(10)-triene-3,16β diol, 15α-methoxy-llβ-fluoro-oestra-1,3,5(10)-triene-3,Ιδβ-diol, 15a-thiomethyl-l^-fluoro-oestra-1,3, 5(10)-triene-3,Ιδβ-diol, 15β-methyl-llβ-fluoro-oestra-1,3, 5(10)-triene-3,16α-diol, 15β-ethyl-llβ-fluoro-oestra, 1,3,5(10)-triene-3,16α-diol, 15β-ρΓορϋ-11β-£ fluoro-oestra-1,3,5(10)-triene-3,16α-diol, 15β-311ϋ-11β-ί1ηοη-03ζίΓ3-1, 3,5(10)-triene-3,16a-diol, 15β-ί-ρΓορϋ-11β-ί1ποη-03Ζ1η3-1,3, 5(10)-triene-3,16a-diol, 15β-i-propenyl-llβ-fluoroestr3-l, 3,5(10)-triene-3,16a-diol, 15β-methoxy-llβ-fluoroestra-1,3,5(10)-triene-3,16a-diol, 15β-thiomethyl-llβ-fluoroestra-l, 3,5(10)-triene-3,16a-diol, 15β-πΐθΐϊ1-11β-ί luor-oestra-1, 3,5 (10)-triene-3, Ιδβ-diol, 15β-θ1ί1-11β-ίluoro-estra-1,3, 5(10)-triene-3, Ιδβ-diol, 15β-ρηορϋ-11β-ίluoro-estra-1,3,5(10)-triene-3,Ιδβ-diol, 15β-311ί1-11β-ίluoro-estra-1,3,5(10)-triene-3, Ιδβ-diol, 15β-ϊ-ρτορί1-11β-£luoro-estra-1,3,5(10)-triene-3,Ιδβ-diol, 15β-ί-ρηορθηϊ1-11β-£1ηοη-03ζ1η3-1, 3,5(10)-triene-3,Ιδβ-diol, 15β-methoxy-11β-fluoro-oestra-1,3, 5(10)-triene-3,Ιδβ-diol, 15β-thiomethyl-11β-fluoro-oestra-1,3, 5(10)-triene-3,Ιδβ-diol,

14α,15α-methylene-7α-phenyl-oestra-l, 3,5(10)-triene-3,16α-diol, β,15β-methylene-7α-phenyl-oestra-1,3,5(10)-triene-3,16α-diol,

14β,15β-methylene-7α-phenyl-oestra-1,3,5(10),8(9)-tetraene-3,16a-diol,

7α-phenyl-oestra-1,3,5(10),8(9)-tetraene-3,16a-diol,

7a-phenyloestra-1,3,5(10),8(14)-tetraene-3,16a-diol,

7-phenyl-oestra-l,3,5(10),6,8-pentaene-3,16a-diol, llβ-Inethoxy-7α-phenyl-oestra-l,3,5(10)-triene-3,16a-diol,

Ιΐβ-fluoro-7α-phenyl-oestra-1,3,5(10)-triene-3,16α-diol,

7a-phenyl-8a-oestra-1,3,5(10)-triene-3,16a-diol,

7a-phenyl-oestra-1,3,5(10)-triene-2,3,16a-triol,

17β-fluoro-7α-phenyl-oestra-1,3,5(10)-triene-3,16a-diol,

18a-homo-7a-phenyl-oestra-1,3,5(10)-triene-3,16a-diol,

18a-homo-7a-phenyl-oestra-1,3,5(10),8(9)-tetraene-3,16a-diol,

18a-homo-14a,15a-methylene-7a-phenyl-oestra-1,3,5(10)-triene-3,16a-diol,

18a-homo-14a,15a-methylene-7a-phenyl-oestra-1,3,5(10),8(9)-tetraene-3, 16a-diol,

18a-homo-14a,15a-methylene-7-phenyl-oestra-1, 3,5(10),6,8-pentaene-3,16a-diol,

14α,15α-methylene-7α-phenyl-oestra-1,3,5(10)-triene-3,Ιδβ-diol,

14β, 15β-ιηθ1ϊ1έη-7α-ίenyl-estra-1,3,5(10)-trien-3,Ιδβ-diol,

14β,15β-methylene-7α-phenyl-oestra-1,3,5(10),8(9)-tetraene-3,Ιδβ-diol,

7a-phenyloestra-1,3,5(10),8(9)-tetraene-3,Ιδβ-diol,

7a-phenyloestra-1,3,5(10),8(14)-tetraene-3,Ιδβ-diol,

7-phenyl-oestra-1,3,5(10),6,8-pentaene-3,Ιββ-diol,

11β-πΐθίοχϊ-7αι enyl-estra-1,3,5 (10)-triene-3, Ιββ-diol,

Ιΐβ-fluoro-7α-phenyl-oestra-1,3,5(10)-triene-3,Ιββ-diol,

7a-phenyl-8a-oestra-1,3,5(10)-triene-3, Ιββ-diol,

7a-phenyl-oestra-1,3,5(10)-triene-2,3,16a-triol,

17β-ίfluoro-7α-phenyl-oestra-1,3,5(10)-triene-3,Ιββ-diol,

18a-homo-7a-phenyl-oestra-1,3,5(10)-triene-3,Ιββ-diol,

18a-homo-7a-phenyl-oestra-1,3,5(10),8(9)-tetraene-3,Ιββ-diol,

18a-homo-14a,15a-methylene-7a-phenyl-oestra-1,3,5(10)-triene-3,Ιββ-diol,

18a-homo-14a,15a-methylene-7a-phenyl-oestra-l, 3,5(10),8(9)-tetraene-3,Ιββ-diol,

18a-homo-14a,la-methylene-7-phenyl-oestra-l, 3,5(10) , 6,8-pentaene-3,Ιδβ-diol,

15a-methyl-7a-phenyl-oestra-1,3,5(10)-triene-3, Ιδα-diol,

15a-ethyl-7a-phenyl-oestra-1,3,5(10)-triene-3,16a-diol,

15a-propyl-7a-phenyl-oestra-1,3,5(10)-triene-3,Ιδα-diol,

15a-allyl-7a-phenyl-oestra-1,3,5(10)-triene-3,Ιδα-diol,

15a-i-propyl-7a-phenyl-oestra-l,3,5(10)-triene-3,16a-diol, 15a-i-propenyl-7a-phenyl-oestra-l,3,5(10)-triene-3,16a-diol 15a-methoxy-7a-phenyl-oestra-l,3,5(10)-triene-3,16a-diol, 15a-thiomethyl-7a-phenyl-oestra-l,3,5(10)-triene-3,16a-diol, 15a-methyl-7a-phenyl-oestra-l,3,5(10)-triene-3,Ιββ-diol, 15a-ethyl-7a-phenyl-oestra-l,3,5(10)-triene-3,Ιββ-diol, 15a-propyl-7a-phenyl-oestra-l,3,5(10)-triene-3,Ιββ-diol, 15a-allyl-7a-phenyl-oestra-l,3,5(10)-triene-3,Ιββ-diol, 15a-i-propyl-7a-phenyl-oestra-l,3,5(10)-triene-3,Ιββ-diol, 15a-i-propenyl-7a-phenyl-oestra-l,3,5(10)-triene-3,Ιββ-diol 15a-methoxy-7a-phenyl-oestra-l,3,5(10)-triene-3,163-diol 15a-thiomethyl-7a-phenyl-oestra-l,3,5(10}-triene-3,Ιββ-diol, 15β-methyl-7α-phenyl-oestra-l,3,5(10)-triene-3,16a-diol, 15β-ethyl-7α-phenyl-oestra-l,3,5(10)-triene-3,16a-diol, 15β-propyl-7α-phenyl-oestra-l,3,5(10)-triene-3,16a-diol, 15β-allyl-7α-phenyl-oestra-l,3,5(10)-triene-3,16a-diol, 15β-i-propyl-7α-phenyl-oestra-l,3,5(10)-triene-3, 16a-diol, 15β-i-propenyl-7α-phenyl-oestra-l,3,5(10)-triene-3,16a-diol 15β-methoxy-7α-phenyl-oestra-l,3,5(10)-triene-3,16α-diol, ^-thiomethyl-7α-phenyl-oestra-l, 3, 5 (10) -triene-3, 16α-diol, ^-methyl-7α-phenyl-oestra-l, 3,5(10) -triene-3, Ιββ-diol,

15p-ethyl-7a-phenyl-oestra-l,3,5(10)-triene-3,Ιββ-diol, ^-propyl-7a-phenyl-oestra-l, 3,5 (10) -triene-3, Ιββ-diol, 15β-311ϊ1-7α-ίβηϋ-03ζΡΓ3-1,3,5(10)-triene-3,Ιββ-diol, ^-i-propyl-7a-phenyl-oestra-l, 3, 5 (10) -triene-3, Ιββ-diol, 15β-i-propenyl-7α-phenyl-oestra-l,3,5(10)-triene-3,Ιββ-diol, ^-methoxy-7a-phenyl-oestra-l, 3,5 (10) -triene-3, Ιββ-diol, 15β-thiomethyl-7α-phenyl-oestra-1,3,5(10)-triene-3, Ιββ-diol, 15α-methyl-1^-fluoro-7α-phenyl-oestra-1, 3,5(10)-triene-3,16α-diol,

15α-ethyl-11β-fluoro-7α-phenyl-oestra-1,3,5(10)-triene-3,16a-diol,

15a-propyl-1,4-fluoro-7a-phenyl-oestra-1,3,5(10)-triene-3,16a-diol,

15a-allyl-11β-fluoro-7a-phenyl-oestra-1,3,5(10)-triene-3,16a-diol,

15a-1-propyl-1,2-fluoro-7a-phenyl-oestra-1,3,5(10)-triene-3,16a-diol,

15a-1-propenyl-1,2-fluoro-7a-phenyl-oestra-1,3,5(10)-triene-3,16a-diol,

35a-methoxy-11β-fluoro-7a-phenyl-oestra-1, 3,5(10)-triene-3,16a-diol,

15a-thiomethyl-1-fluoro-7a-phenyl-oestra-1,3,5(10)-triene-3,16a-diol,

15a-methyl-lip-fluoro-7a-phenyl-oestra-l, 3,5(10)-triene-3,16β-diol,

15a-ethyl-1^-fluoro-7a-phenyl-oestra-1,3,5(10)-triene-3,16β-diol,

15a-propyl-1^-fluoro-7a-phenyl-oestra-1,3,5(10)-triene-3,16β-diol,

15α-311ί1-11β-fluoro-7α-phenyl-oestra-1,3,5(10)-triene-3,16β-diol,

15a-i-Propyl-1^-fluoro-7a-phenyl-oestra-1,3,5(10)-triene-3,Ιδβ-diol,

15α-i-propenyl-11β-fluoro-7α-phenyl-oestra-1,3,5(10)-triene-3,Ιδβ-diol,

15a-methoxy-1^-fluoro-7a-phenyl-oestra-1,3,5(10)-triene-3,16β-diol,

15a-thiomethyl-1^-fluoro-7a-phenyl-oestra-1,3,5(10)-triene-3,Ιδβ-diol,

15β^θίί1-11β-ί fluoro-7α-phenyl-oestra-1,3,5(10)-triene-3,16α-diol,

15β-θϋ1-11β-£fluoro-7a-phenyl-oestra-1,3, 5(10)-triene-3, 16a-diol,

15β-ρΓορί1-11β-£fluoro-7α-phenyl-oestra-1,3,5(10)-triene-3,16α-diol,

15β-311ϊ1-11β-ίfluoro-7aa-phenyl-oestra-1,3,5(10)-triene-3, 16a-diol, ⁹⁹ _{: ;} ·· :;··:···

15β-ί-ρΓορί1-11β-ίluoro-7a-phenyl-estra-l, 3,5(10)-triene-3,16a-diol,

15β-i-propenyl-11β-fluoro-7a-phenyl-oestra-1,3,5(10)-triene-3,16a-diol,

15β-methoxy-11β-fluoro-7α-phenyl-oestra-1, 3,5(10)-triene-3,16α-diol,

15β-thioInethyl-11β-fluoro-7β-phenyl-oestra-1,3,5(10)-triene-3,16a-diol,

15β-ιηθίϊ1-11β-ίfluoro-7α-phenyl-oestra-l, 3,5 (10) -triene-3,16β-diol,

15β-βίί1-11β-ί1υοΓ-7β-ίβηϋ-03ΖίΓ3-1,3,5(10)-triene-3,16β-diol,

15β-propyl-11β-fluoro-7α-phenyl-oestra-1, 3,5(10)-triene-3,16β-diol,

15β-311ϋ-11β-ί fluoro-7aa-phenyl-oestra-l, 3,5(10)-triene-3,16β-diol,

15β-i-propyl-11β-fluoro-7α-phenyl-oestra-1,3,5(10)-triene-3,16β-όίο1,

15β-i-propenyl-11β-fluoro-7β-phenyl-oestra-1,3,5(10)-triene-3,16β-όϊο1,

15β-methoxy-11β-fluoro-7α-phenyl-oestra-1,3,5(10)-triene-3,16β

-diol,

100

15β-1 iometh ϋ-ΙΙβ-fluoro-7α-phenyl-oestra-1, 3,5(10)-triene-3,16βdiol, «

11β-[2-(3-methylthien)-yl]-oestra-1, 3,5(10)-triene-3,16a-diol,

11β—[2-(3-methylthien)-yl]-oestra-1, 3,5(10)-triene-3,Ιββ-diol,

13a-oestra-1,3,5(10)-triene-3,16a-diol,

13a-oestra-1,3,5(10)-triene-3,Ιββ-diol,

14β-oestra-1,3,5(10)-triene-3,16a-diol,

14β-03ζ1η3-1,3,5(10)-triene-3,Ιββ-diol,

Ιΐβ-methyl-oestra-1,3,5(10)-triene-3,16a-diol,

Iΐβ-methyl-oestra-1,3,5(10)-triene-3, Iββ-diol,

11β-methyl-18a-homoestra-1,3,5(10)-triene-3,16a-diol, 11β-methyl-18a-homoestra-1,3,5(10)-triene-3,Ιββ-diol,

Ιΐβ-ethyl-oestra-1,3,5(10)-triene-3,16a-diol,

Ιΐβ-ethyl-oestra-l,3,5(10)-triene-3,Ιββ-diol, llβ-ethyl-18α-homoestra-l,3,5(10)-triene-3,16α-diol, llβ-ethyl-18α-homoestra-l,3,5(10)-triene-3, Ιββ-diol,

Ιΐβ-vinyl-oestra-1,3,5(10)-triene-3,16a-diol,

Ιΐβ-vinyl-oestra-1,3,5(10)-triene-3, Ιββ-diol, Ιλβ-vinyl-18α-homoestra-1,3,5(10)-triene-3,16α-diol, Ιλβ-vinyl-18α-homoestra-1,3,5(10)-triene-3,Ιββ-diol, Ιΐβ-ethinyl-oestra-1,3,5(10)-triene-3, 16α-diol,

101

Ιΐβ-ethynyl-oestra-l,3,5(10)-triene-3,Ιδβ-diol, llβ-ethynyl-18a-homoestra-l, 3,5(10)-triene-3,16a-diol, lip-ethynyl-18a-homoestra-l,3,5(10)-triene-3,16β-diol, 9a-methyl-oestra-l,3,5(10)-triene-3,16a-diol, 9a-methyl-oestra-l,3,5(10)-triene-3,Ιδβ-diol, 9a-methyl-18a-homoestra-l, 3,5(10)-triene-3,16a-diol, 9a-methyl-18a-homoestra-l, 3,5(10)-triene-3,Ιδβ-diol, 7a-methyl-18a-homoestra-l, 3,5(10)-triene-3,16a-diol, 7a-methyl-18a-homoestra-l, 3,5(10)-triene-3,16a-diol, 7a-ethyl-18a-homoestra-l, 3,5(10)-triene-3,16a-diol, 7a-ethyl-18a-homoestra-l, 3,5(10)-triene-3,16a-diol, 7a-ethyl-18a-homoestra-l, 3,5(10)-triene-3,16a-diol, 7α,Ιΐβ-dimethyl-oestra-l, 3, 5(10)-triene-3,16a-diol,

7α,Ιΐβ-dimethyl-oestra-l, 3,5(10)-triene-3,Ιδβ-diol,

7α, 11β-diInethyl-18a-homoestra-l, 3,5(10)-triene-3,16a-diol, 7α, 11β-dimethyl-18a-homoestra-1,3,5(10)-triene-3,16a-diol, 16β-ethynyl-18a-homoestra-l, 3,5 (10) -triene-3,16a-diol, 16a-ethynyl-18a-homoestra-l, 3,5(10)-triene-3,Ιδβ-diol, 7a-methyl-16p-ethynyl-estra-l,3,5(10)-triene-3,16a-diol, 7α-methyl-16α-ethynyl-estra-1,3,5(10)-triene-3,Ιδβ-diol, 7α-methyl-16β-ethynyl-18α-homoestral-1, 3,5(10)-triene-3,16α-diol

7α-methyl-16α-ethynyl-18α-homoestra-1,3,5(10)-triene-3,16β-diol,

102 llp-Methyl-16p-ethynyl-oestra-l,3,5(10)-triene-3,16a-diol, lip-methyl-16a-ethynyl-oestra-l, 3,5(10)-triene-3, Ιββ-diol, llβ-methyl-16β-ethynyl-18a-homoestra-l,3,5(10)-triene-3,16α-diol, l^-methyl-16a-ethynyl-18a-homoestra-l, 3,5(10) -triene-3,16β

-diol.

Claims (52)

103 PATENT CLAIMS 1. 16-dihydroxy-oestra-1,3,5/10/-trienes of general formula (I); in this formula, the substituents R ^x -R ¹⁷ independently have the following meanings: R ¹ is a halogen atom, a hydroxy, methyl, trifluoromethyl, methoxy, ethoxy group or a hydrogen atom, R ² is a halogen atom, a hydroxy group, a straight or branched chain, saturated or unsaturated alkoxy group with up to 6 carbon atoms, or a hydrogen atom, R ⁴ is a halogen atom, a straight or branched chain, saturated or unsaturated alkyl group with up to 10 carbon atoms, a trifluoromethyl or pentafluoroethyl group, a straight or branched chain, saturated or unsaturated alkoxy group with up to 6 carbon atoms or a hydrogen atom, R ⁷ is a halogen atom in the α- or β-position, an α- or β-position straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkyl group having up to 10 carbon atoms, a straight or branched chain, saturated or unsaturated alkoxy group having up to 6 carbon atoms, an optionally substituted aryl or heteroaryl group or a hydrogen atom, R ⁸ is a hydrogen atom in the α- or β-position, a straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkyl group in the α- or β-position with up to 10 carbon atoms, or a cyano group in the α- or β-position, 104 —· ·..· λ. .L'· R ⁹ is a hydrogen atom in the α- or β-position, a methyl·-, ethyl-, trifluoromethyl- or pentafluoroethyl group in the α- or β-position, R ¹¹ is a nitroxy, hydroxy or mercapto group in the α- or β-position, a halogen atom in the α- or β-position, a chloromethyl group in the α- or β-position, a straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkyl group in the α- or β-position, a straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkoxy or alkylthio group in the α- or β-position, a straight or branched chain, saturated or unsaturated, alkylthio group in the α- or β-position, an optionally substituted aryl or heteroaryl group or a hydrogen atom, R ¹³ is a methyl, ethyl, trifluoromethyl or pentafluoroethyl group in the α- or β-position, and R ¹⁴ is a straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkyl group with up to 10 carbon atoms in the α- or β-position or a hydrogen atom in the α- or β-position, R ¹⁵ is a halogen atom in the α- or β-position, a straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkyl group of up to 10 carbon atoms in the α- or β-position, which may be interrupted by one or more oxygen, sulfur, sulfoxide or sulfone groups or a group of the formula =NR ¹⁵ ', or a hydrogen atom and R ¹⁵ is hydrogen, methyl, ethyl, propyl or isopropyl, or: ·.· Λ * * ' · * « R ¹⁴ and R ¹⁵ together represent a 14α,15α-methylene or 14p-15P-methylene group optionally substituted with 1 or 2 halogen atoms, R ¹⁶ is a hydrogen atom in the α- or β-position, a straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkyl group with up to 10 carbon atoms in the α- or β-position, a trifluoromethyl or pentafluoroethyl group, a cyanomethyl group, R ¹⁷ is a halogen atom in the a- or p-position, max. a straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkyl group, hydrogen atom or hydroxyl group having 10 carbon atoms, in which the dotted line in the B, C and D rings optionally represents one or more double bonds, while the wavy line indicates that the given substituent is in the α- or β-position, with the exception of the following compounds: oestra-1,3,5/10/-triene-3,16α-diol, oestra-1,3,5/10/-triene-3,16β-0ϊο1, oestra-1,3,5/10/,7-tetraene-3,16α-diol, oestra-1,3,5/10/,7-tetraene-3,16β-diol, 16α-ethynyl-oestra-1,3,5/10/-triene-3,16β-diol and 16β-ethynyl-oestra-1, 3,5/10/-triene-3,16α-diol. 2. Compounds according to claim 1, in which the substituents R ¹ -R ¹⁷ independently have the following meanings: R ¹ is a fluorine atom, a hydroxy, methyl, trifluoromethyl, methoxy, ethoxy group or a hydrogen atom, 106 Γ .··. ,; _... ..... : - · *·-. *·· ' '· ·*. w .W* R is a fluorine atom, a hydroxy, methoxy or ethoxy group or a hydrogen atom, R is fluorine, methyl, ethyl, trifluoromethyl, methoxy, ethoxy or hydrogen, R is a fluorine atom in the α- or β-position, a methyl, ethyl, propyl or i-propyl group in the α- or β-position, an optionally substituted aryl group, a trifluoromethyl group in the α- or β-position or a hydrogen atom, θ R is a hydrogen atom in the α- or β-position, a methyl or ethyl group in the α- or β-position, R is a hydrogen atom in the α- or β-position, a methyl, ethyl, trifluoromethyl or pentafluoromethyl group in the α- or β-position, R is a nitroxy, hydroxy group or fluorine atom in the α- or β-position, a chloromethyl group in the α- or β-position, a methyl, methoxy, phenyl or 3-methylthien-2-yl group in the α- or β-position or a hydrogen atom, R ¹³ is a methyl or ethyl group in the α- or β-position, and R is a hydrogen atom in the α- or β-position or a methyl group in the α- or β-position and R ¹⁵ is a fluorine atom in the α- or β-position, a methyl group in the α- or β-position or a hydrogen atom, or R and R ¹⁵ together form a 14α, 15α- methylene or 14β, ^-methylene group, R is methyl, ethyl, ethynyl, propynyl or trifluoromethyl, 107 R ¹⁷ is a fluorine atom in the α- or β-position, a methyl group, a hydroxy group or a hydrogen atom, and the dashed lines in rings B, C and D optionally represent an additional double bond between carbon atoms 9 and 11. 3. Compounds of general formula (I) according to claim 1, wherein R ⁷ is a halogen atom in the α- or β-position, an α- or β-position straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkyl group having up to 10 carbon atoms, a straight or branched chain, saturated or unsaturated alkoxy group having up to 6 carbon atoms, an optionally substituted aryl or heteroaryl group and all other substituents are hydrogen atoms, 4. Compounds of general formula (I) according to claim 1, wherein R ¹¹ is a nitroxy, hydroxy or mercapto group in the α- or β-position, a halogen atom in the α- or β-position, a chloromethyl group in the α- or β-position, a straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkyl group in the α- or β-position, a straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkoxy or alkylthio group in the α- or β-position, a straight or branched chain, saturated or unsaturated, optionally substituted aryl or heteroaryl group and all other substituents are hydrogen atoms. 5. Compounds of general formula (I) according to claim 1, wherein 108 R ¹⁵ is a halogen atom in the α- or β-position, a straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkyl group of up to 10 carbon atoms in the α- or β-position, which may be interrupted by one or more oxygen, sulfur, sulfoxide or sulfone groups or an imino group of the formula =NR ¹⁵ ', where R ¹⁵ ' represents a hydrogen atom, methyl, ethyl, propyl or i-propyl, and all other substituents represent a hydrogen atom. 6. Compounds of general formula (I) according to claim 1, wherein R ⁷ is a halogen atom in the α- or β-position, an α- or β-position straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkyl group having up to 10 carbon atoms, a straight or branched chain, saturated or unsaturated alkoxy group having up to 6 carbon atoms, an optionally substituted aryl or heteroaryl group, R ¹¹ is a nitroxy, hydroxy or mercapto group in the α- or β-position, a halogen atom in the α- or β-position, a chloromethyl group in the α- or β-position, a straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkyl group in the α- or β-position, a straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkoxy or alkylthio group in the α- or β-position, a straight or branched chain, saturated or unsaturated, optionally substituted aryl or heteroaryl group and all other substituents are hydrogen atoms. 109 7. Compounds of general formula (I) according to claim 1, wherein R ⁷ is a halogen atom in the α- or β-position, an α- or β-position straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkyl group having up to 10 carbon atoms, a saturated or unsaturated straight or branched chain alkoxy group having up to 6 carbon atoms, an optionally substituted aryl or heteroaryl group, R ¹⁵ or a halogen atom in the β-position, a straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkyl group of up to 10 carbon atoms in the α- or β-position, which may be interrupted by one or more oxygen, sulfur, sulfoxide or sulfone groups or an imino group of the formula =NR ¹⁵ , where R ¹⁵ 'is hydrogen, methyl, ethyl, propyl or i-propyl, and all other substituents are hydrogen. 8. Compounds of general formula (I) according to claim 1, wherein R ^{11 is a} nitroxy, hydroxy or mercapto group in the ~ or β-position, a halogen atom in the α or β-position, a chloromethyl group in the α or β-position, a straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkyl group in the α or β-position, a straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkoxy or alkylthio group in the α or β-position, a straight or branched chain, saturated or unsaturated, alkylthio group in the α or β-position, an optionally substituted aryl or heteroaryl group, 110 R ¹⁵ is a halogen atom in the α- or β-position, a straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkyl group of up to 10 carbon atoms in the α- or β-position, which may be interrupted by one or more oxygen, sulfur, sulfoxide or sulfone groups or an imino group of the formula =NR ¹⁵ ', where R ¹⁵ 'is hydrogen, methyl, ethyl, propyl or i-propyl, and all other substituents are hydrogen. 9. Compounds of general formula (I) according to claim 1, wherein R ⁷ is a halogen atom in the α- or β-position, a linear or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl group in the α- or β-position, a linear or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl group in the α- or β-position, a linear or branched, saturated or unsaturated, optionally partially or fully fluorinated alkoxy group in the α- or β-position, an optionally substituted aryl or heteroaryl group, ^{r11 is a} nitroxy, hydroxy or mercapto group in the α- or β-position, a halogen atom in the α- or β-position, a chloromethyl group in the α- or β-position, a linear or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl group in the α- or β-position, a linear or branched, saturated or unsaturated, alkoxy or alkylthio group in the α- or β-position, an optionally substituted aryl or heteroaryl group, R ¹⁵ is a halogen atom in the α- or β-position, a straight or branched chain of up to 10 carbon atoms in the α- or β-position, saturated or unsaturated, III is an optionally partially or fully fluorinated alkyl group which may be interrupted by one or more oxygen, sulfur, sulfoxide or sulfone groups or an imino group of the formula =NR ¹⁵ ', where R ¹⁵ 'is hydrogen, methyl, ethyl, propyl or i-propyl, and all other substituents are hydrogen. 10. Compounds of general formula (I) according to claim 1, wherein the dashed lines represent one or more conjugated double bonds. 11. Compounds of general formula (I) according to claim 1, in which the carbon atoms at positions 6 and 7 are linked by a double bond. 12. Compounds of general formula (I) according to claim 1, in which the carbon atoms at positions 7 and 8 are linked by a double bond. 13. Compounds of general formula (I) according to claim 1, in which the carbon atoms at positions 8 and 9 are linked by a double bond. 14. Compounds of general formula (I) according to claim 1, in which the carbon atoms at positions 9 and 11 are linked by a double bond. 15. Compounds of general formula (I) according to claim 1, in which the carbon atoms at positions 8 and 14 are linked by a double bond. 112 16. Compounds of general formula (I) according to claim 1, in which the carbon atoms at positions 11 and 12 are linked by a double bond. 17. Compounds of general formula (I) according to claim 1, in which the carbon atoms at positions 14 and 15 are linked by a double bond. 18. Compounds of general formula (I) according to claim 1, in which the carbon atoms at positions 6 and 7, and 8 and 9 are linked by a double bond. 19. Compounds of general formula (I) according to claim 1, in which the carbon atoms at positions 8 and 9, and 14 and 15 are linked by a double bond. 20. Compounds of general formula (I) according to claim 1, in which the carbon atoms at positions 6 and 7, 8 and 9, and 11 and 12 are linked by a double bond. 21. Compounds of general formula (I) according to claim 1, in which the carbon atoms at positions 6 and 7, 8 and 9, and 14 and 15 are linked by a double bond. 22. Compounds of general formula (I) according to claim 1, in which the carbon atoms at positions 6 and 7, 8 and 9, 11 and 12, and 14 and 15 are linked by a double bond. 23. Compounds of general formula (I) according to any one of claims 1 to 22, in which the -OH group located on the carbon atom at position 3 and 16 or one of them is esterified with an aliphatic or aromatic carboxylic acid or an α- or β-amino acid. 24. Compounds of general formula (I) according to claim 1, listed after Table 2. 113 25. The following compounds of general formula (I) according to claim 24: 7a-fluoro-oestra-1,3,5(10)-triene-3,16a-diol, 7a-methyl-oestra-1,3,5(10)-triene-3,Ιββ-diol, 7a-methyl-oestra-1,3,5(10)-triene-3,16a-diol, 18a-homo-oestra-1,3,5(10)-triene-3,16a-diol, 7a-phenyl-oestra-1,3,5(10)-triene-3,Ιββ-diol, 7β-£θηϋ-03ζ1Γ3-1, 3,5(10) -triene-3, Ιββ-diol, 7β-phenyl-oestra-1, 3,5(10)-triene-3,16a-diol, 7a-ethyl-oestra-1,3,5(10)-triene-3, Ιββ-diol, 7β-θίϊ1-03ζίΓ3-1,3,5(10)-triene-3,16a-diol, 7β-ethyl-oestra-1,3,5(10)-triene-3,Ιββ-diol. 26. Use of 3,16-dihydroxy-oestra-1,3,5/10/-triene derivatives of the general formula (I') for the preparation of a medicament for the treatment of diseases and conditions caused by estrogen deficiency in humans, wherein the substituents R ^x -R ¹⁷ independently have the following meanings: R ¹ is a halogen atom, a hydroxy, methyl, trifluoromethyl, methoxy, ethoxy group or a hydrogen atom, R is a halogen atom, a hydroxy group, a straight or branched chain, saturated or unsaturated alkoxy group with up to 6 carbon atoms or a hydrogen atom, R ^is a halogen atom, a straight or branched chain, saturated or unsaturated alkyl group with up to 10 carbon atoms, a trifluoromethyl or pentafluoroethyl group, a straight or branched chain, saturated or unsaturated alkoxy group with up to 6 carbon atoms or a hydrogen atom, R ⁷ is a halogen atom in the α- or β-position, an α- or β-position straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkyl group having up to 10 carbon atoms, a saturated or unsaturated straight or branched chain alkoxy group having up to 6 carbon atoms, an optionally substituted aryl or heteroaryl group or a hydrogen atom, R ⁸ is a hydrogen atom in the α- or β-position, a straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkyl group in the α- or β-position with up to 10 carbon atoms, or a cyano group in the α- or β-position, R ⁹ is a hydrogen atom in the α- or β-position, a methyl, ethyl, trifluoromethyl or pentafluoroethyl group in the α- or β-position, ^{r11 is a} nitroxy, hydroxy or mercapto group in the α- or β-position, a halogen atom in the α- or β-position, a chloromethyl group in the α- or β-position, a straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkyl group in the α- or β-position, a straight or branched chain, saturated or unsaturated alkoxy or alkylthio group in the α- or β-position, a straight or branched chain, saturated or unsaturated alkoxy or alkylthio group in the α- or β-position, an optionally substituted aryl or heteroaryl group or a hydrogen atom, R is a methyl, ethyl, trifluoromethyl or pentafluoroethyl group in the α or β position, & and R ¹⁵ 'is hydrogen, methyl, ethyl, propyl or i-propyl, or R ¹⁴ and R ¹⁵ together are a 14α,15α-methylene or 14β-15β-methylene group optionally substituted with 1 or 2 halogen atoms, R ¹⁶ is a hydrogen atom in the α- or β-position, a straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkyl group of up to 10 carbon atoms in the α- or β-position, a trifluoromethyl or pentafluoroethyl group, a cyanomethyl group, or a hydrogen atom in the α- or β-position, R ¹⁷ is a halogen atom in the α- or β-position, a straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl group of up to 10 carbon atoms, a hydroxy group or a hydrogen atom, and the dashed lines in the B, C and D rings optionally indicate one or more double bonds, and the wavy lines indicate the α- or β-position of the substituents. 27. Use according to claim 26 for symptoms associated with peri- and post-menopause. 28. Use according to claim 26 for symptoms associated with peri- and post-andropause. 29. Use according to claim 27 for preventing and alleviating symptoms of hot flashes, sleep disorders, irritability, mood swings, incontinence, vaginal atrophy and mood disorders caused by hormone deficiency. 30. Use according to claim 29 for the prevention and alleviation of symptoms of diseases of the urogenital tract. 31. Use according to claim 26 for the prevention and alleviation of symptoms of gastrointestinal diseases. 116 32. Use according to claim 31 for the prevention and alleviation of symptoms of ulcers and bleeding metastases in the gastrointestinal tract. 33. Use according to claim 32 for the prevention and alleviation of symptoms of metastases. 34. The use according to claim 26 for influencing male infertility in vitro. 35. The use according to claim 26 for influencing male infertility in vivo. 36. Use according to claim 26 for influencing female infertility in vitro. 37. The use according to claim 26 for influencing female infertility in vivo. 38. The use according to claim 26 for hormone replacement. 39. Use according to claim 26 for alleviating symptoms caused by hormone deficiency in cases of ovarian dysfunction due to surgery, medication or other causes. 40. Use according to claim 26 for preventing and influencing bone mass loss caused by hormone deficiency. 41. Use according to claim 40 for preventing and influencing osteoporosis. 42. Use according to claim 26 for preventing and influencing circulatory disorders of the heart. 43. Use according to claim 26 for preventing and influencing diseases of the vascular system. 117 44. Use according to claim 43 for preventing and influencing atherosclerosis. 45. Use according to claim 43 for preventing and influencing hyperplasias regenerating in capillaries. 46. Use according to claim 26 for preventing and influencing neurodegenerative diseases caused by hormone deficiency. 47. Use according to claim 26 for preventing and influencing Alzheimer's disease and the deterioration of memory and learning caused by hormone deficiency. 48. Use according to claim 26 for influencing inflammatory diseases and diseases of the immune system. 49. Use according to claim 26 for preventing and controlling benign prostatic hyperplasia. 50. The use of partial formula (II) as a constituent part of the full formula of compounds which show a difference in their estrogenic effect on the bones compared to their effect on the uterus in favor of the former effect. 51. Use of the sub-formula (II') of claim 50, wherein the substituents are independently as follows: R ¹ is a halogen atom, a hydroxy, methyl, trifluoromethyl, methoxy, ethoxy group or a hydrogen atom, R ² is a halogen atom, a hydroxy group, a straight or branched chain, saturated or unsaturated alkoxy group with up to 6 carbon atoms or a hydrogen atom, R ⁴ is a halogen atom, a straight or branched chain, saturated or unsaturated alkyl group with up to 10 carbon atoms, a trifluoromethyl group or 118 pentafluoroethyl group, a straight or branched chain, saturated or unsaturated alkoxy group with up to 6 carbon atoms or a hydrogen atom, R ⁷ ' a halogen atom in the α- or β-position, a straight or branched chain, saturated or unsaturated alkyl group in the α- or β-position with up to 10 carbon atoms, optionally partially or fully fluorinated, a straight or branched chain, saturated or unsaturated alkoxy group with up to 6 carbon atoms, an optionally substituted aryl or heteroaryl group or a hydrogen atom, R ^8, a hydrogen atom in the α- or β-position, a straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkyl group with up to 10 carbon atoms in the α- or β-position, or a cyano group in the α- or β-position, Q f R is a hydrogen atom in the α- or β-position, a methyl, ethyl, trifluoromethyl or pentafluoroethyl group in the α- or β-position, R ¹¹ is a nitroxy, hydroxy or mercapto group in the α- or β-position, a halogen atom in the α- or β-position, a chloromethyl group in the α- or β-position, a straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkyl group in the α- or β-position, a straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkoxy or alkylthio group in the α- or β-position, a straight or branched chain, saturated or unsaturated, optionally substituted aryl or heteroaryl group or hydrogen atom, R ¹³ is a methyl, ethyl, trifluoromethyl or pentafluoroethyl group in the oc- or β-position, and 119 R ¹⁴ ' is a straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkyl group of up to 10 carbon atoms in the a- or β-position, or a hydrogen atom in the a- or β-position, R ¹⁵ ' is a halogen atom in the a- or β-position, a straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkyl group of up to 10 carbon atoms in the a- or β-position, which is an alkyl group or hydrogen atom interrupted by one or more oxygen, sulfur, sulfoxide or sulfone groups or an imino group of the formula =NR ¹⁵ ', where R ¹⁵ ' represents a hydrogen atom, a methyl, ethyl, propyl or i-propyl group, or R ¹⁴ ' and R ¹⁵ ' together represent a 14α,15α-methylene or 14β-15β-methylene group optionally substituted with 1 or 2 halogen atoms, R ¹⁶ ' is a hydrogen atom in the α- or β-position, a straight or branched chain, saturated or unsaturated, optionally partially or fully fluorinated alkyl group in the α- or β-position with up to 10 carbon atoms, a trifluoromethyl or pentafluoroethyl group, R ¹⁷ ' is a halogen atom in the α- or β-position, a straight or branched, saturated or unsaturated, optionally partially or fully fluorinated alkyl group of up to 10 carbon atoms, a hydroxy group or a hydrogen atom, and the dashed lines in the B, C and D rings optionally indicate one or more double bonds, and the wavy lines indicate the α- or β-position of the substituents. 120 52. Pharmaceutical compositions comprising at least one compound according to any one of claims 1 to 25 and a pharmaceutically acceptable carrier. The authorized person: t I *<^2 .AukLó A'u Ká.